Tropane analogs and methods for inhibition of monoamine transport

ABSTRACT

New tropane analogs that bind to monoamine transporters are described, particularly, 8-aza, 8carbo and 8-oxo tropanes having 6- or 7- substituents. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers. Certain preferred compounds of the present invention have a high selectivity for the DAT versus the SERT. Also described are pharmaceutical therapeutic compositions comprising the compounds formulated in a pharmaceutically acceptable carrier and a method for inhibiting 5-hydroxy-tryptamine reuptake of a monoamine transporter by contacting the monoamine transporter with a 5-hydroxytryptamine reuptake inhibiting amount of a compound of the present invention. Preferred monoamine transporters for the practice of the present invention include the dopamine transporter, the serotonin transporter and the norepinephrine transporter.

This application is a division of Ser. No. 09/314,441 filed May 19,1999, which is a division of Ser. No. 08/893,921 filed Jul. 11, 1997,now U.S. Pat. No. 5,948,933, and is a continuation-in-part of Ser. No.08/552,584 filed Nov. 3, 1995, now U.S. Pat. No. 6,171,576.

This invention was supported by NIH Grant Nos. DA48309, DA06303 andDA09462, and Contract NO1DA 7-8081 and Grant RO1DA 11542, which aresupported by the National Institute on Drug of Abuse (NIDA). Thegovernment has certain rights to this invention.

FIELD OF THE INVENTION

This invention relates to tropane analogs of cocaine and their use asinhibitors of monoamine reuptake.

BACKGROUND OF THE INVENTION

Cocaine dependence is a problem of national significance. To date nococaine pharmacotherapy has been reported. Cocaine is a potent stimulantof the mammalian central nervous system. Its reinforcing properties andstimulant effects are associated with its propensity to bind tomonoamine transporters, particularly the dopamine transporter (DAT).(Kennedy, L. T. and I. Hanbauer (1983), J. Neurochem. 34: 1137-1144;Kuhar, M. J., M. C. Ritz and J. W. Boja (1991), Trends Neurosci. 14:299-302; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R.D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B.K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1990), PharmacolBiochem. Behav. 35: 949-953; Reith, M. E. A., B. E. Meisler, H. Sershenand A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R.J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223;Schoemaker, H., C. Pimoule, S. Arbilla, B. Scatton, F. Javoy-Agid and S.Z. Langer (1985), Naunyn-Schmiedeberg's Arch. Pharmacol. 329: 227-235.)It also binds with substantial potency to serotonin transporters (SERT)and norepinephrine transporters.

Structure activity relationship (SAR) studies have largely focused on aseries of cocaine analogs. Among the more potent of these congeners at³H-cocaine binding sites in striatum (Madras, B. K., M. A. Fahey, J.Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp.Ther. 251: 131-141; Reith, M. E. A., B. E. Meisler, H. Sershen and A.Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129) is(1R)-3β-(4-fluorophenyl)tropane-2β-carboxylic acid methyl ester,(WIN35,428 or CFT) (Kaufman, M. J. and B. K. Madras (1992), Synapse 12:99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D.Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141) reported in 1973(Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973),J. Med. Chem. 16: 1260-1267). This compound was subsequentlyradiolabeled to provide a selective probe for the DAT in primate brain.(Canfield, D. R., R. D. Spealman, M. J. Kaufman and B. K. Madras (1990),Synapse 6: 189-195; Kaufman, M. J. and B. K. Madras (1991), Synapse 9:43-49; Kaufman, M. J., R. D. Spealman and B. K. Madras (1991), Synapse9: 177-187.)

Among the most potent tropane inhibitors of monoamine binding sites instriatum are3β-{4-(1-methylethenyl)phenyl}-2β-propanoyl-8-azabicyclo(3.2.1)octane,(Bennett, B. A., C. H. Wichems, C. K. Hollingsworth, H. M. L. Davies, C.Thornley, T. Sexton and S. R. Childers (1995), J. Pharm. Exp. Ther. 272:1176-1186; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T.Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558)(1R)-RTI55 (βCIT), (Boja 1991; Boja, J. W., A. Patel, F. I. Carroll, M.A. Rahman, et al. (1991), Eur. J. Pharmacol. 194: 133-134; Neumeyer, J.L., S. Wang, R. A. Milius, R. M. Baldwin, et al. (1991), J. Med. Chem.34: 3144-3146) (1R)-RTI121, (Carroll, F. I., A. H. Lewin, J. W. Boja andM. J. Kuhar (1992), J. Med. Chem. 35: 969-981.) and(1R)-3β-(3,4-dichlorophenyl)-tropane-2β-carboxylic acid methyl ester(O-401), (Carroll, F. I., M. A. Kuzemko and Y. Gao (1992), Med. ChemRes. 1: 382-387; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R.Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862).

SAR studies of the binding of these agents and their effects onmonoamine transporter function have been reported. (Blough, B. E., P.Abraham, A. H. Lewin, M. J. Kuhar, J. W. Boja and F. I. Carroll (1996),J. Med. Chem. 39: 4027-4035; Carroll, F. I., P. Kotian, A. Dehghani, J.L. Gray, et al. (1995), J. Med. Chem. 38: 379-388; Carroll, F. I., A. H.Lewin, J. W. Boja and M. J. Kuhar (1992),y J. Med. Chem. 35: 969-981;Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao, et al. (1994),J. Med. Chem. 37: 2865-2873; Chen, Z., S. Izenwasser, J. L. Katz, N.Zhu, C. L. Klein and M. L. Trudell (1996), J. Med. Chem. 39: 4744-4749;Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton andS. R. Childers (1996), J. Med. Chem. 39: 2554-2558; Davies, H. M. L.,Z.-Q. Peng and J. H. Houser (1994), Tetrahedron Lett. 48: 8939-8942;Davies, H. M. L., E. Saikali, T. Sexton and S. R. Childers (1993), Eur.J. Pharmacol. Mol. Pharm. 244: 93-97; Holmquist, C. R., K. I.Keverline-Frantz, P. Abraham, J. W. Boja, M. J. Kuhar and F. I. Carroll(1996), J. Med. Chem 39: 4139-4141; Kozikowski, A. P., G. L. Araldi andR. G. Ball (1997), J. Org. Chem. 62: 503-509; Kozikowski, A. P., M.Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunningham andK. M. Johnson (1992), J. Med. Chem. 35: 4764-4766; Kozikowski, A. P., D.Simoni, S. Manfredini, M. Roberti and J. Stoelwinder (1996), TetrahedronLett. 37: 5333-5336; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R.Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862; Meltzer, P.C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010;Meltzer, P. C., A. Y. Liang and B. K. Madras (1996), J. Med. Chem. 39:371-379; Newman, A. H., A. C. Allen, S. Izenwasser and J. L. Katz(1994), J. Med Chem. 37: 2258-2261; Newman, A. H., R. H. Kline, A. C.Allen, S. Izenwasser, C. George and J. L. Katz (1995), J. Med. Chem. 38:3933-3940; Shreekrishna, V. K., S. Izenwasser, J. L. Katz, C. L. Klein,N. Zhu and M. L. Trudell (1994), J. Med. Chem. 37: 3875-3877; Simoni,D., J. Stoelwinder, A. P. Kozikowski, K. M. Johnson, J. S. Bergmann andR. G. Ball (1993), J. Med. Chem. 36: 3975-3977.)

Binding of cocaine and its tropane analogs to monoamine transporters isstereoselective. As example (1R)-(−)-cocaine binds at the dopaminetransporter about 200-fold more potently than the unnatural isomer,(1S)-(+)-cocaine. (Kaufman, M. J. and B. K. Madras (1992), Synapse 12:99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D.Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K.,R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius(1989), Mol. Pharmacol. 36: 518-524; Reith, M. E. A., B. E. Meisler, H.Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz,M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237:1219-1223.)

Also, only the R-enantiomers of cocaine have been found active in avariety of biological and neurochemical measures. (Clarke, R. L., S. J.Daum, A. J. Gambino, M. D. Aceto, et al. (1973), J. Med. Chem. 16:1260-1267; Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111;Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D.Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K.,R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius(1989), Mol. Pharmacol. 36: 518-524; Reith, M. E. A., B. E. Meisler, H.Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz,M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237:1219-1223; Sershen, H., M. E. A. Reith and A. Lajtha (1980),Neuropharmacology 19: 1145-1148; Sershen, H., M. E. A. Reith and A.Lajtha (1982), Neuropharmacology 21: 469-474; Spealman, R. D., R. T.Kelleher and S. R. Goldberg (1983), J. Pharmacol. Exp. Ther. 225:509-513.) Parallel stereoselective behavioral effects have also beenobserved. (Bergman, J., B. K. Madras, S. E. Johnson and R. D. Spealman(1989), J. Pharmacol. Exp. Ther. 251: 150-155; Heikkila, R. E., L.Manzino and F. S. Cabbat (1981), Subst. Alcohol Actions/Misuse 2:115-121; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha(1986), Biochem. Pharmacol. 35: 1123-1129; Spealman, R. D., R. T.Kelleher and S. R. Goldberg (1983), J. Pharmacol. Exp. Ther. 225:509-513; Wang, S., Y. Gai, M. Laruelle, R. M. Baldwin, B. E. Scanlet, R.B. Innis and J. L. Neumeyer (1993), J. Med. Chem. 36: 1914-1917.) Forexample, in primates and rodents the stimulating and reinforcingproperties of the (−)-enantiomer of cocaine or its 3-aryltropane analogswere considerably greater than for the (+)-enantiomers.

Although SAR studies of cocaine and its 3-aryltropane analogs haveoffered insight into their mode of binding to monoamine transporters, acomprehensive picture of the binding interaction at the molecular levelhas not emerged. SAR studies on the classical tropane analogs (Carroll,F. I., Y. Gao, M. A. Rahman, P. Abraham, et al. (1991), J. Med. Chem.34: 2719-2725; Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao,et al. (1994), J. Med. Chem. 37: 2865-2873; Madras, B. K., M. A. Fahey,J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp.Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L.Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36:518-524; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh andB. K. Madras (1993), J. Med. Chem. 36: 855-862; Reith, M. E. A., B. E.Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35:1123-1129) appeared to provide a consistent model for this interactionwith the DAT, however, subsequent studies revealed inconsistencies.(Carroll, F. I., P. Kotian, A. Dehghani, J. L. Gray, et al. (1995), J.Med. Chem. 38: 379-388; Chen, Z., S. Izenwasser, J. L. Katz, N. Zhu, C.L. Klein and M. L. Trudell (1996), J. Med. Chem. 39: 4744-4749; Davies,H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R.Childers (1996), J. Med. Chem. 39: 2554-2558; Kozikowski, A. P., G. L.Araldi and R. G. Ball (1997), J. Org. Chem. 62: 503-509; Meltzer, P. C.,A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010;Meltzer, P. C., A. Y. Liang and B. K. Madras (1996), J. Med. Chem. 39:371-379.)

Carroll had proposed (Boja, J. W., R. M. McNeill, A. Lewin, P. Abraham,F. I. Carroll and M. J. Kuhar (1992), Mol. Neurosci. 3: 984-986;Carroll, F. I., P. Abraham, A. Lewin, K. A. Parham, J. W. Boja and M. J.Kuhar (1992), J. Med. Chem. 35: 2497-2500; Carroll, F. I., Y. Gao, M. A.Rahman, P. Abraham, et al. (1991), J. Med. Chem. 34: 2719-2725; Carroll,F. I., M. A. Kuzemko and Y. Gao (1992), Med. Chem Res. 1: 382-387) fourmolecular requirements for binding of cocaine and its tropane analogs atthe DAT: a 2β-carboxy ester, a basic nitrogen capable of protonation atphysiological pH, the R-configuration of the tropane and a 3β-aromaticring at C₃. However, Davies (Davies, H. M. L., E. Saikali, T. Sexton andS. R. Childers (1993), Eur. J. Pharmacol. Mol. Pharm. 244: 93-97) laterreported that introduction of 2β-ketones did not reduce potency.Kozikowski questioned the role of hydrogen bonding at the C₂ sitebecause introduction of unsaturated and saturated alkyl groups(Kozikowski, A. P., M. Roberti, K. M. Johnson, J. S. Bergmann and R. G.Ball (1993), Bioorg. Med. Chem. Lett. 3: 1327-1332; Kozikowski, A. P.,M. Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunninghamand K. M. Johnson (1992), J. Med. Chem. 35: 4764-4766) did not diminishbinding. Further, the ionic bond between a protonated amine (atphysiologically pH) and the presumed (Kitayama, S., S. Shimada, H. Xu,L. Markham, D. H. Donovan and G. R. Uhl (1993), Proc. Natl. Acad. Sci.U.S.A. 89: 7782-7785) aspartate residue on the DAT was questionedbecause reduction of nitrogen nucleophilicity (Kozikowski, A. P., M. K.E. Saiah, J. S. Bergmann and K. M. Johnson (1994), J. Med. Chem. 37(37):3440-3442) by introduction of N-sulfones did not reduce binding potency.

It also has been reported (Madras, B. K., J. B. Kamien, M. Fahey, D.Canfield, et al. (1996), Pharmacol Biochem. Behav. 35: 949-953) thatintroduction of an alkyl or allyl group did not eliminate bindingpotency. An N-iodoallyl group on the tropane has provided potent andselective ligands for the DAT, and altropane is currently beingdeveloped as a SPECT imaging agent (Elmaleh, D. R., B. K. Madras, T. M.Shoup, C. Byon, et al. (1995), J. Nucl. Chem., 37 1197-1202 (1966);Fischman, A. J., A. A. Bonab, J. W. Babich, N. M. Alpert, et al. (1996),Neuroscience-Net 1, 00010, (1997). A ^(99m)technetium labeled compound,technepine, which binds potently and selectively to the DAT and providesexcellent in vivo SPECT images has been reported. (Madras, B. K., A. G.Jones, A. Mahmood, R. E. Zimmerman, et al. (1996), Synapse 22: 239-246.)(Meltzer, P. C., Blundell, P., Jones, A. G., Mahmood, A., Garada, B. etal., J. Med. Chem., 40, 1835-1844, (1997).2-Carbomethoxy-3-(bis(4-fluorophenyl)methoxy)tropanes have been reported(Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37:2001-2010). The S-enantiomer,(S)-(+)-2β-carbomethoxy-3α-(bis(4-fluorophenyl)methoxy)tropane(Difluoropine) was considerably more potent (IC₅₀: 10.9 nM) andselective (DAT v. SERT: 324) than any of the other seven isomers,including the R-enantiomers.

Drug therapies for cocaine abuse are needed. Also, there is a need forprotective agents for neurodegenerative diseases such as Parkinson'sdisease and Alzheimer's disease as well as therapeutic agents fordopamine related dysfunction such as Attention Deficit Disorder.Compounds that inhibit monoamine reuptake in the mammalian system aresought to provide such therapies.

Inhibition of 5-hydroxytryptamine reuptake has an effect on diseasesmediated by 5HT receptors. Compounds that provide such inhibition can beuseful, for example, as therapeutic anti-depressants.

Cocaine recognition sites are localized on monoamine transporters suchas, for example, the dopamine transporter (DAT) and serotonintransporter (SERT). These transporters are localized, in turn, onmonoamine nerve terminals. Compounds that bind to these sites can beuseful as (i) probes for neuro-degenerative diseases (e.g., Parkinson'sdisease), (ii) therapeutic drugs for neurodegenerative diseases (e.g.,Parkinson's and Alzheimer's disease), (iii) therapeutic drugs fordopamine dysfunction (e.g., Attention Deficit Disorder), (iv) treatmentof psychiatric dysfunction (e.g., depression) and (v) treatment ofclinical dysfunction (e.g., migraine).

SUMMARY OF THE INVENTION

The compounds of this invention are new tropane analogs that bind tomonoamine transporters. Thus, the present invention provides tropaneanalogs having one of the following formula:

wherein:

R₁=COOCH₃, COR₃, lower alkyl, lower alkenyl, lower alkynyl, CONHR₄, orCOR₆;

R₂=is a 6α, 6β, 7α or 7β substituent, which can be selected from OH,OR₃, F, Cl, Br, and NHR₃;

X=NR₃, CH₂, CHY, CYY₁, CO, O, S; SO, SO₂, NSO₂R₃, or C=CX₁Y with the N,C, O or S atom being a member of the ring;

X₁=NR₃, CH₂, CHY, CYY₁ CO, O, S; SO, SO₂, or NSO₂R₃;

R₃=H, (CH₂)_(n)C₆H₄Y, C₆H₄Y, CHCH₂, lower alkyl, lower alkenyl or loweralkynyl;

Y and Y₁=H, Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN, NHCOCH₃, N(CH₃)₂,(CH₂)nCH₃, COCH₃, or C(CH₃)₃;

R₄=CH₃, CH₂CH₃, or CH₃SO₂;

R₆=morpholinyl or piperidinyl;

Ar=phenyl-R₅, naphthyl-R₅, anthracenyl-R₅, phenanthrenyl-R₅, ordiphenylmethoxy-R₅;

R₅=Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN, NHCOCH₃, N(CH₃)₂,(CH₂)nCH₃, COCH₃, C(CH₃)₃ where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I,3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-dioAc, 3,4-diOCH₃, 3-OH-4-Cl,3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl,lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);

R₆=morpholinyl or piperidinyl;

m=0 or 1;

n=0, 1, 2, 3, 4 or 5; and

when X is an oxygen atom or contains a carbon atom as the ring member,R₂ can be H;

except that when X=N, R₁ is not COR₆.

The substituents at the 2 and 3 position of the ring can be α- or β-.Although R₁ is illustrated in the 2- position, it should be recognizedthat substitution at the 3- position is also included and the positionis dependent on the numbering of the tropane ring. The compounds of thepresent invention can be racemic, pure R-enantiomers, or pureS-enantiomers. Thus, the structural formulas illustrated herein areintended to represent each enantiomer and diastereomer of theillustrated compound.

The compounds of the present invention can be radiolabelled, forexample, to assay cocaine receptors. Certain preferred compounds of thepresent invention have a high selectivity for the DAT versus the SERT.

The present invention also provides pharmaceutical therapeuticcompositions comprising the compounds formulated in a pharmaceuticallyacceptable carrier.

Further, the invention provides a method for inhibiting5-hydroxytryptamine reuptake of a monoamine transporter by contactingthe monoamine transporter with a 5-hydroxy-tryptamine reuptakeinhibiting (5-HT inhibiting) amount of a compound of the presentinvention. Inhibition of 5-hydroxy-tryptamine reuptake of a monoaminetransporter in a mammal is provided in accord with the present inventionby administering to the mammal a 5-HT inhibiting amount of a compound ofthe present invention in a pharmaceutically acceptable carrier.Preferred monoamine transporters for the practice of the presentinvention include the dopamine transporter, the serotonin transporterand the norepinephrine transporter.

In a preferred embodiment, the invention also provides a method forinhibiting dopamine reuptake of a dopamine transporter by contacting thedopamine transporter with a dopamine reuptake inhibiting amount of acompound of the present invention. Inhibition of dopamine reuptake of adopamine transporter in a mammal is provided in accord with the presentinvention by administering to the mammal a dopamine inhibiting amount ofa compound of the present invention in a pharmaceutically acceptablecarrier.

The term “lower alkyl” when used herein designates aliphatic saturatedbranched or straight chain hydrocarbon monovalent substituentscontaining from 1 to about 8 carbon atoms such as methyl, ethyl,isopropyl, n-propyl, n-butyl, (CH₂)_(n)CH₃, C(CH₃)₃; etc., morepreferably 1 to 4 carbons. The term “lower alkoxy” designates loweralkoxy substituents containing from 1 to about 8 carbon atoms such asmethoxy, ethoxy, isopropoxy, etc., more preferably 1 to 4 carbon atoms.

The term “lower alkenyl” when used herein designates aliphaticunsaturated branched or straight chain vinyl hydrocarbon substituentscontaining from 2 to about 8 carbon atoms such as allyl, etc., morepreferably 2 to 4 carbons. The term “lower alkynyl” designates loweralkynyl substituents containing from 2 to about 8 carbon atoms, morepreferably 2 to 4 carbon atoms such as, for example, propyne, butyne,etc.

The terms substituted lower alkyl, substituted lower alkoxy, substitutedlower alkenyl and substituted lower alkynyl, when used herein, includecorresponding alkyl, alkoxy, alkenyl or alkynyl groups substituted withhalide, hydroxy, carboxylic acid, or carboxamide groups, etc. such as,for example, —CH₂OH, —CH₂CH₂COOH, —CH₂CONH₂, —OCH₂CH₂OH, —OCH₂COOH,—OCH₂CH₂CONH₂. etc. As used herein, the terms lower alkyl, lower alkoxy,lower alkenyl and lower alkynyl are meant to include where practicalsubstituted such groups as described above.

When X contains a carbon atom as the ring member, reference to X issometimes made herein as a carbon group. Thus, when X is a carbon group,as that phrase is used herein, it means that a carbon atom is a ringmember at the X position (i.e., the 8-position).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a chemical reaction scheme for producing 6- or 7-substituted tropane analogs (Scheme 1).

FIG. 2 illustrates a reaction scheme for the preparation of3-diarylmethoxytropanes (Scheme 2) using a 7-substituted, 3β-ketotropane to make the corresponding 7β-OH compound.

FIG. 3 illustrates a reaction scheme for the preparation of8-oxatropanes (Scheme 3).

FIG. 4 illustrates an alternative reaction scheme for the preparation of8-oxatropanes (Scheme 4).

FIG. 5 illustrates a reaction scheme for the preparation of 3-aryl(substituted)-8-oxatropanes (Scheme 5).

FIG. 6 illustrates a reaction scheme for the preparation of2-carbomethoxy-3-aryl-8-oxabicyclo(3.2.1)octenes (Scheme 6).

FIG. 7 illustrates a reaction scheme for the preparation of8-carbatropanes (Scheme 7).

DETAILED DESCRIPTION OF THE INVENTION

In accord with the present invention, novel tropane compounds areprovided that bind to monoamine transporters, preferably the DAT.Certain preferred compounds also have a high selectivity for the DATversus the SERT. In one preferred embodiment of the present invention,tropane analogs are provided having substituents in the 6- or 7-position of the tropane structure. Preferred compounds of thisembodiment of the invention include those having the formula:

where X, Ar, R₂ and m have the same meaning as defined above.Particularly preferred compounds have X includes a nitrogen, carbon oroxygen atom as a ring member, R₂ is hydrogen, hydroxy or methoxy, and Aris phenyl, substituted phenyl such as mono- or di-halogen substitutedphenyl, or a diarylmethoxy including halogen substituted such groups.

For example, 6- and 7-hydroxy-8-azatropanes of the present invention canbe prepared as shown in Scheme 1 (FIG. 1). Synthesis of these 6- and 7-oxygenated tropanes in accord with Scheme 1 is based upon a Mannichreaction. (Robinson, R. (1917), J. Chem. Soc. 111: 762.)Dimethoxydihydrofuran 1, is stirred for 12 h (hours) in 3N HCl and thenneutralized by addition of aqueous NaOH. Methylamine hydrochloride inwater, and acetone-dicarboxylic acid anhydride 2 in MeOH are added. Amixture of 6- and 7-hydroxy, 3β-keto esters 3 and 4 is obtained. The exo(β) stereochemistry of the hydroxyl group at C₆ (3), or C₇ (4), isconfirmed by NMR studies.

Chromatographic separation also provides 6- and 7-methoxy compounds 12and 13. The 6- and 7- hydroxy β-keto esters 3 and 4 are eachmethoxymethylated with dimethoxymethane and pTSA to provide 5. Althoughboth 6- and 7-substituted compounds are taken through the followingsequence of reactions, Scheme 1 illustrates the reaction scheme for the7-substituted compound. Subsequent conversion (Carroll, F. I., P.Kotian, A. Dehghani, J. L. Gray, et al. (1995), J. Med. Chem. 38:379-388; Keverline, K. I., P. Abraham, A. H. Lewin and F. I. Carroll(1995), Tetrahedron Lett. 36: 3099-3102) to the enol triflate 6 isachieved with sodium bistrimethylsilyl amide and phenyl triflimide. Thealkenes 7 are then obtained (85%) by Suzuki coupling of the triflateswith 3,4-dichlorophenyl boronic acid. Reduction of 7 with SmI₂ at −78°C., in the presence of MeOH, and subsequent chromatography affords thesaturated tropanes, 8 (61%) and 9 (20%). Compound 8 exists in atwist-boat conformation while compound 9 assumes a twist-chairconformation. Finally, the methoxymethyl (MOM) group of each of 8 and 9is removed in high yield (85%) with trimethylsilyl bromide in CH₂Cl₂ at0° C. to give the corresponding hydroxy tropanes 10 and 11. (Chen, Z.,S. Izenwasser, J. L. Katz, N. Zhu, C. L. Klein and M. L. Trudell (1996),J. Med. Chem. 39: 4744-4749; #214.) The alkene 7 can be treated in thesame manner to remove the MOM group at that stage and provide a 6- or7-substituted unsaturated tropane analog.

Esters can be obtained by acylation with suitable acid chlorides oranhydrides. The 7- (and 6-) methoxy, 3β-keto esters 12 (and 13) aretransformed into their enol triflates and analogous transformations thenprovide the methoxy tropanes 14 and 15.

Biological data for representative2-carbomethoxy-3-(3,4-diphenyltropanes of the present invention areshown in Table 1.

TABLE 1 Inhibition of ³H-WIN35,428 binding to the DAT and ³H-citaloprambinding to the SERT: cynomolgus monkey caudate-putamen IC₅₀ (nMSelectivity Compound R DAT SERT DATV.SERT 10 3α (boat) OH 1 1,450 1,45011 3β (chair) OH 1 20 20 15 3α (bcat) OCH₃ 92 5,215 57 14 3β (chair)OCH₃ 86 884 10

The 7-OH compounds can exhibit extremely potent and selective bindingfor the DAT. Thus, compound 10 manifests an IC₅₀<2 nM and highselectivity (DAT v. SERT>500) and the 3β compound 11 is equally potentat the DAT (IC₅₀=1 nM) but less selective (DAT v. SERT=20). Whereas theparent compound 2-carbomethoxy-3,4-di-chlorophenyltropane is potent,(IC₅₀=1.09 nM) but lacks selectivity (DAT v. SERT=2), the 7β-hydroxycompounds surprisingly retain potency and are also considerably moreselective (DAT v. SERT=20 for 3β (chair), =1450 for 3α (boat)).Introduction of the 7β-hydroxyl group has significantly and unexpectedlyimproved the selectivity of these compounds for the DAT.

These compounds are racemic. The pure enantiomers, compound 10 andcompound 11, are synthesized enantiopure. Resolution is achieved byformation of the diastereomeric tartrate salts of compound 5 or byformation and separation of diastereomeric enol camphanates. Thus, thetartrate salt of protected (MOM or AcO) compound 5 is recrystallized bystandard methods, well known to those skilled in the art, to provideeach of the diastereomeric salts. Treatment with base providesenantiopure (1R)-compound 5 and (1S)-compound 5. Alternatively,formation of the diastereomeric enol camphanates esters of compound 5,recrystalization, and hydrolysis with LiOH also provides enantiopure(1R) -compound 5 and (1S)-compound 5. These enantiopure ketones arecarried through the sequence to provide the enantiopure targetcompounds. Thus, 3β (chair) and 3α (boat) hydroxytropanes or variousanalogous alkoxytropanes can be prepared.

The potency of the 7-hydroxy and 7-methoxy anaologs of2-carbomethoxy-3-(3,4-diphenyl tropane, 3β (chair) and 3α (boat), shownin Table 1, were determined by the Dopamine Transporter Assay andSerotonin Transporter Assay described hereinafter.

The preparation of 3-diarylmethoxytropanes is illustrated in Scheme 2using a 7-substituted, 3β-keto tropane to make the corresponding 7β-OHcompound (see FIG. 2). The 7α-OH (as well as 6α-OH and 6β-OH) compoundsare carried through an identical sequence. Other 3-aryloxytropanes canbe made by analogous reaction schemes. Synthesis of the 7β-OH compound21 is based upon prior synthetic routes. Thus, the MOM protected(1S)-keto ester 5 is reduced with LiBH(Bu^(i))₃ in tetrahydrofuran (THF)to provide the 2β-COOCH₃-3α-OH compound 19. Alternatively, reduction canbe conducted with NaBH₄, to provide a mixture of the 2α, 2β, and 3α, 3βsubstituted compounds. The 2α-COOCH₃-3α-OH compound can be inverted upontreatment with NaHCO₃ to provide the preferred 2β-COOCH₃-3α-OH 19.Reaction of compound 19 with diarylmethyl chloride (van der Zee 1980)gives the MOM protected compound 20 which is deprotected withtrimethylsilyl bromide (TMSBr) in CH₂Cl₂ to yield the desired targetcompounds 21. The aryl ring can be substituted with one or more halideatoms, preferably chloride or iodide, hydroxy groups, nitro groups,amino groups including mono- and di- alkyl substituted groups havingfrom 1-8 carbon atoms, cyano groups, lower alkyl groups having from 1-8carbon atoms, lower alkoxy groups having from 1-8 carbon atoms, loweralkenyl groups having from 2-8 carbon atoms, lower alkynyl groups havingfrom 2-8 carbon atoms, and combinations of such substituents. Preferredaryl groups have substituents including Br, Cl, I, F, OH, OCH₃, CF₃,NO₂, NH₂, CN, NHCOCH₃, N(CH₃)₂, (CH₂)_(n)CH₃ where n=0-6, COCH₃,C(CH₃)₃, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl,3,4-diOH, 3,4-diOAc, 3,4-diOCH₃, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH,3-F-4-OH, allyl, isopropyl and isobutyl.

Potent “6,7-bridge” hydroxy compounds of the tropane analogs of thepresent invention, e.g., the 8-aza family, can be demethylated andrealkylated with a variety of alkyl and alkyl aryl groups. Thus, forexample 21 is treated with ACE-Cl to provide the nor compound ordemethylation can be conducted prior to deprotection by treatment of 20with ACE-Cl in presence of 2,6-lutidine. Reaction with suitable alkylchlorides in the presence of K₂CO₃ or alternately with KF/celite thenprovides N-substituted compounds such as N-(CH₂)_(n)-Ar (n=1-3;Ar=phenyl or halophenyl). The MOM group is removed with TMSBr.

8-oxatropanes, in accord with the present invention, can be potentinhibitors of monoamine transporters. 6- and 7-Hydroxy-8-oxa-3-aryltropanes are particularly preferred compounds of the present invention.Examples of such preferred compounds of the present invention have thefollowing formula:

where R is preferably H, 4-F, 4-Cl, 4-Br, 4-I, 4-CH₃, or the aryl groupis a 3,4 dihalo substituted phenyl such as, for example, 3,4-dichloro.

The syntheses of 8-oxatropanes can be accomplished by either of the tworoutes (Schemes 3 and 4) illustrated herein. Thus, following Scheme 3(FIG. 3), the ketone 22, prepared as described by Lampe and Hoffman(Chem. Commun. (1996): 1931-1932) is protected as the ketal 23 (ethyleneglycol, p-toluene sulfonic acid (pTSA)) and then hydroborated withLiBH(Bu^(i))₃ (Bu^(i)=iso-butyl) followed by oxidative work-up withalkaline H₂O₂ (Lautens, M. and S. Ma (1996), Tetrahedron Lett. 37:1727-1730) to provide the ketone 24 (X=H). Protection withdimethoxymethane and pTSA then provides protected compound 24 (X=MOM).Introduction of the 2-COOCH₃ group is effected with dimethylcarbonateand sodium hydride (Meltzer, P. C., A. Y. Liang and B. K. Madras (1994),J. Med. Chem. 37: 2001-2010) to provide compound 25 (X=MOM).Introduction of this 2-COOCH₃ group is not specific. However, this is anadvantage because racemic 2-COOCH₃-oxabicycles, both 6- and 7-substituted, are obtained. These positional isomers are separable bycolumn chromatography. Resolution is accomplished through the enolcamphanate route described earlier. Conversion to the enol triflate 26is accomplished with sodium bistrimethylsilyl amide and phenyltriflimide. Suzuki coupling of the triflates with the relevant arylboronic acid obtains the alkenes 27. Reduction of 27 with SmI₂ at −78°C., with MeOH as the proton source, and subsequent chromatographyaffords the saturated protected oxabicycles 28 and 29. Finally, the MOMgroup of each of 28 and 29 is removed with trimethylsilyl bromide inCH₂Cl₂ at 0° C. to give the corresponding hydroxy tropanes 28 (X=H) and29 (X=H). Deprotecting compound 27 can make the correspondingunsaturated oxatropanes.

Alternatively, using the longer route (Scheme 4), the ketone 22 isconverted to the benzyl protected alcohol 31. Both the (−)-compound 31and the (+)-compound 31 have been prepared in >96% ee by use of(−)-(Ipc)₂BH or (+)-(Ipc)₂BH respectively. (Lampe, T. F. J. and H. M. R.Hoffmann (1996), Chem. Commun.: 1931-1932.) Protection of the hydroxygroup with dimethoxymethane and pTSA provides compound 32 (X=MOM).Catalytic hydrogenolysis then provides the 3-ol compound 33. Oxidationunder mild Dess-Martin conditions (Dess, D. B. and J. C. Martin (1983).J. Org. Chem. 48: 4155) gives the desired ketones 34 (X=MOM) which arecarried through the sequence described above to provide compounds 28 and29.

In another preferred embodiment of the present invention, preferred8-oxatropanes and 8-carbatropanes include those having alkenyl andalkynyl groups on the 3-aryl ring, particularly of the 2-COOCH₃tropanes, to enhance potency at the SERT. Particularly preferredexamples of such compounds have the following formula:

where X is an oxygen or a carbon group such as, for example, CH₂, CHY,CYY₁, CO, or C=CX₁Y where X₁, Y and Y₁ are defined above, and R₇ is alower alkenyl or lower alkynyl group having from about 2 to about 8carbon atoms. Particularly preferred lower alkenyl and lower alkynylgroups are ethenyl, propenyl, butenyl, propynyl, butynyl andmethylpropynyl.

Introduction of such functionality in the 8-oxa compounds can beaccomplished following the reported synthetic route for the 8-azacompounds. (Blough, B. E., P. Abraham, A. H. Lewin, M. J. Kuhar, J. W.Boja and F. I. Carroll (1996), J. Med. Chem. 39: 4027-4035.) Iodocompounds are prepared as precursors for the 4-alkenyl and 4-alkynylcompounds shown in Scheme 5 (see FIG. 5). Reduction of the octenes 47(Scheme 6) (R=I) with SmI₂ in THF/MeOH at −78° C. provides a mixture ofthe 3β and 3α compounds 35. In general, when trifluoroacetic acid isused, the major products are the 2β, 3α-boat conformers. The minorproducts are the 2β, 3β-chair conformers. With water as proton source, a1:1 mixture is generally obtained. Chemical shift, coupling constants,and nuclear Overhauser effect (“nOe”) analyses confirm that the2β-carbomethoxy compounds are exclusively obtained upon SmI₂ reductionof the octenes. Only 3β compounds are presented in the scheme. However,compounds in 3α and 3β conformation are similarly prepared. Racematesand enantiopure compounds can also be prepared by similar techniqueswell known to those skilled in the art. Compound 35 is reacted with CuIand bis(triphenylphosphine)palladium (II) chloride and trimethylsilylacetylene. The product is desilylated with t-butyl ammoniumfluoride to provide the 4-alkynyl compounds 39 a. The same reaction,using propyne, provides compound 39 b, although no deprotection isrequired here. Reduction of compound 39 b over Lindlar's catalyst at 60psi provides the Z-ene 40. The E-ene 38 is obtained via the allylcompound 37. Thus, compound 35 is reacted with allyltributyltin andtetrakis(triphenyl-phosphine)palladium to provide compound 37, which isquantitatively isomerized to compound 38.

Compounds 36 a and b are prepared upon reaction of compound 35, in thepresence of ZnCl₂ and bis(triphenylphosphine) palladium (II) chloride,with vinylmagnesium bromide, or 2-bromopropene and n-butyl lithium,respectively.

The 3α compounds are obtained by identical chemistry. Also, theenantiopure end-products required are carried through identicalchemistry for 3α and 3β diastereomers starting with enantiopure compound35 obtained from enantiopure ketones (1R)-45 and (1S)-45. Conformationaland configurational assignments demonstrate that the carbomethoxy is inthe 2β-configuration. Further, the 3α vs. 3β conformers are readilyidentified.

A comparison of the binding potency of the 8-oxabicycles with the8-azabicycles shows that, although the most potent in both classes arealmost equipotent (IC₅₀=1-3 nM), the less potent compounds (R=H, F) aretypically weaker in the 8-oxa than 8-aza series.

The enol triflate is reacted with the appropriate poly-aromatic boronicacids (Thompson, W. J. and J. Gaudino (1984), J. Org. Chem. 49:5237-5243) to provide the 2,3-enes. SmI₂ reduction gives 3α and 3βconformers:

where X is an oxygen atom or a carbon group, Ar is preferably4-substituted phenyl, naphthyl, anthracenyl or phenanthrenyl and R ispreferably lower alkyl, lower alkoxy or amino, as defined above. Thecompounds are prepared as racemates and pairs of enantiomers.

Enantiomers and diastereomers can be separated by silica gelchromatography using 2% ammonia in ethyl acetate as the eluent, or othersolvent systems as necessary. Compounds from the above series arehydrolyzed (LiOH) and treated with oxalyl chloride followed by aminessuch as morpholine or piperidine to provide amides

2,3- (and 3,4-) Unsaturated 8-aza- and 8-oxa-tropanes are additionalpreferred embodiments of the present invention. Examples of preferredsuch compounds have the following formula:

where X is preferably oxygen, N-alkyl or a carbon moiety, R ispreferably morpholinyl, piperidinyl or methoxy, Ar is preferably phenylor naphthyl either of which can be substituted with halogen, alkenylhaving 2-8 carbon atoms or alkynyl having 2-8 carbon atoms such as, forexample, 4-Cl, 4-F, 4-Br, 4-I, 3,4-Cl₂, ethenyl, propenyl, butenyl,propynyl, butynyl, etc.

The synthesis of the 2,3-unsaturated 8-aza- and 8-oxa-tropanes isexemplified in Scheme 6 (see FIG. 6). The 3-(substitutedaryl)-8-oxabicyclo(3.2.1)octanes can be obtained from the keto ester 45.Thus, 2,5-dimethoxytetrahydrofuran 43 is reacted with1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene 44 in CH₂Cl₂ in thepresence of TiCl₄ to give the ketone 45. The ketone 45 is then convertedto compound 46 by reaction with N-phenyltrifluoromethanesulfonimide andsodium bis(trimethylsilyl)amide in THF. The enol triflate 46 is coupledwith arylboronic acids in the presence oftris(dibenzylidene-acetone)dipalladium(0) to provide the aryl octenes47.

Compounds 47 e and f are synthesized from enantiopure compound (1R)-45and compound (1S)-45. Alternatively, a diastereomeric mixture of enolcamphanates is prepared upon reaction of compounds (1R/S)-45 with(S)-(−)-camphanyl chloride in THF. recrystalization from CH₂Cl₂/hexanethen gives the pure diastereomer (1R)-enol camphanate as evidenced byNMR. The residual mixture of enol camphanate diastereomers is treatedwith LiOH to produce compounds (1R/1S)-45 which is then reacted with(R)-(+)-camphanyl chloride. recrystalization of this enol camphanatethen gives the pure (1S) -enol camphanate diastereomer. Quantitativehydrolysis of the enantiomerically pure individual camphanate esterswith LiOH provides ketones (1s)-45 and (1R)-45 (chiral HPLC CC column:(1R)-45 and (1S)-45 >96% ee for each of the enantiomers). The purifiedenantiomers are then subjected to the sequence of steps describedearlier to obtain the enantiomerically pure 8-oxatropene analogs, 27 eand f (see Scheme 3, FIG. 3). Absolute configuration was confirmed byX-ray structural analysis. Isomerization of the 2,3-ene to provide the3,4-enes is achieved with base.

Biological data for representative 2,3-enes of the present inventionhaving a 3-(3,4-dichloro)phenyl substituent are shown in Table 2.

TABLE 2 Inhibition of ³H-W1N35,428 binding to the DAT and ³H-citaloprambinding to the SERT in cynomolgus monkey caudate-putamen. IC₅₀ (nM)Selectivity Compound R/S DAT SERT DATV.SERT 47e 8-0 (1R) 4.6 2,120 46147f 8-0 (1S) 58.2 46,730 802 48 8-NCH₃ (1R) 1.1 867 790

The (1R) enantiomer 47 e binds potently to the DAT (IC₅₀=4.6 nM) andvery weakly at the SERT (IC₅₀=2,120 nM) and is ca. 460-fold selective.Surprisingly and unexpectedly, the (1S) enantiomer 47 f retains potency(DAT: IC₅₀=58.2 nM) and substantial selectivity DAT/SERT=800). The8-amine analogs of these compounds can be prepared via analogous enoltriflate chemistry. Thus, 2-carbomethoxytropane-2-one is similarlyconverted to its enol triflate and coupled with 3,4-dichlorophenylboronic acid to provide compound 48. Compound 48 is among the mostpotent and selective (790-fold) compounds (DAT IC₅₀=1.1 nM; SERTIC₅₀=867 nM). These compounds offer an opportunity to differentiatebinding to the SERT vs. the DAT, as well as to take advantage of thedifferent biological profiles (biological t_(½), toxicity, metabolism)that these compounds offer.

In accord with another preferred embodiment of the present invention,the 2,3- (and 3,4-) didehydro tropanes and 8-oxatropanes have beenhydroxylated or alkoxylated at the 6- and 7- positions to providecompounds capable of intramolecular hydrogen bonding to the 8-oxa and8-aza positions. The selectivity observed in the 2,3-ene and the 7-OHcompounds provides synergism and offers extremely potent and selectivecompounds. The 7β-hydroxy tropanes 10 and 11 are potent and selective.The (1R) 2,3-ene enantiomer 47 e binds potently and selectively to theDAT and the (1R) 8-aza-2,3-ene 48 is among the most potent and selectiveDAT inhibitors. Compounds exhibiting both functionalities areparticularly preferred. The conversion of an enol triflate via Suzukicoupling with appropriate arylboronic acids provides the preferredcompounds (see also Scheme 1, FIG. 1). Such compounds, i.e.,bicyclo(3.2.1)octanes, include compounds having the following formula:

where X is preferably O, NCH₃ or CH₂, R is preferably morpholinyl,piperidinyl or methoxy, R₂ is preferably hydroxy or methoxy in the 6- or7- position, Ar is preferably phenyl or naphthyl either of which can besubstituted with halogen, alkenyl having 2-8 carbon atoms or alkynylhaving 2-8 carbon atoms such as, for example, 4-Cl, 4-F, 4-Br, 4-I,3,4-Cl₂, ethenyl, propenyl, butenyl, propynyl, butynyl, etc.

These compounds can be prepared either as free bases or as apharmacologically active salt thereof such as hydrochloride, tartrate,sulfate, naphthalene-1,5-disulfonate or the like.

The present invention also provides pharmaceutical compositions,preferably comprising the compounds of the present invention in apharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known to those skilled in the art. In a preferredembodiment, the pharmaceutical composition is a liquid composition inpyrogen-free, sterilized container or vial. The container can be unitdose or multidose.

The compounds and pharmaceutical preparations of the present inventioncan be used to inhibit the 5 -hydroxytryptamine reuptake of a monoaminetransporter, particularly reuptake by the dopamine transporter,serotonin transporter or norepinephrine transporter. An effective doseof the compound is administered to a patient based on IC₅₀ valuesdetermined in vitro. The route of administration can be varied but isprincipally selected from intravenous, nasal and oral routes. Theeffective dose can vary depending upon the mode of administration as iswell known in the art.

Dysfunction of dopamine neurons has been implicated in severalneuropsychiatric diseases. Imaging of the dopamine neurons offersimportant clinical information relevant to diagnosis and therapeutictreatments. Dopamine neurons produce dopamine, release theneurotransmitter and remove the released dopamine with a dopaminetransporter protein. Compounds that bind to the dopamine transporter areeffective measures of dopamine neurons and can be transformed intoimaging agents for PET and for SPECT imaging. In identifying a suitablecompound for the dopamine transporter, an essential first step is tomeasure the affinity and selectivity of a candidate at the dopaminetransporter. The affinity is measured by conducting radioreceptorassays. A radiolabeled marker for the transporter, e.g., (³H)WIN 35,428,is incubated with the unlabeled candidate and a source of thetransporter, usually brain striatum. The effect of variousconcentrations of the candidate on inhibiting (3H)WIN 35,428 binding isquantified. The concentration of the compound that inhibits 50% of(³H)WIN 35,428 bound to the transporter (IC₅₀ value) is used as ameasure of its affinity for the transporter. A suitable range ofconcentrations of the candidate typically is 1-10 nM.

It is also important to measure the selectivity of the candidate of thedopamine compared with the serotonin transporter. The serotonintransporter is also detectable in the striatum, the brain region withthe highest density of dopamine neurons and in brain regions surroundingthe striatum. It is necessary to determine whether the candidatecompound is more potent at the dopamine than the serotonin transporter.If more selective (>10-fold), the probe will permit accurate measures ofthe dopamine transporter in this region of interest or will provideeffective treatment modality for the dopamine transporter. Therefore, ameasure of probe affinity of the serotonin transport is conducted byassays paralleling the dopamine transporter assays. (³H)Citalopram isused to radiolabel binding sites on the serotonin transporter andcompetition studies are conducted with the candidate compound at variousconcentrations in order to generate an IC₅₀ value.

This invention will be illustrated further by the following examples.These examples are not intended to limit the scope of the claimedinvention in any manner. The Examples provide suitable methods forpreparing compounds of the present invention. However, those skilled inthe art may make compounds of the present invention by any othersuitable means. As is well known to those skilled in the art, othersubstituents can be provided for the illustrated compounds by suitablemodification of the reactants.

All exemplified target compounds are fully analyzed (mp, TLC, CHN, GCand/or HPLC) and characterized (¹H NMR, ¹³C NMR, MS, IR) prior tosubmission for biological evaluation. The affinity of all the compoundsfor the DAT, SERT and NET are measured. NMR spectra are recorded on aBruker 100, a Varian XL 400, or a Bruker 300 NMR spectrometer.Tetramethylsilane (“TMS”) is used as internal standard. Melting pointsare uncorrected and are measured on a Gallenkamp melting pointapparatus. Thin layer chromatography (TLC) is carried out on Baker Si250F plates. Visualization is accomplished with iodine vapor, UVexposure or treatment with phosphomolybdic acid (PMA). Preparative TLCis carried out on Analtech uniplates Silica Gel GF 2000 microns. Flashchromatography is carried out on Baker Silica Gel 40 mM. ElementalAnalyses are performed by Atlantic Microlab, Atlanta, Ga. and are within0.496 of calculated values for each element. A Beckman 1801Scintillation Counter is used for scintillation spectrometry. 0.1%Bovine Serum Albumin (“BSA”) and (−)-cocaine is purchased from SigmaChemicals. All reactions are conducted under an inert (N₂) atmosphere.

³H-WIN 35,428 (³H-CFT,2β-carbomethoxy-3β-(4-fluorophenyl)-N-³H-methyltropane, 79.4-87.0Ci/mmol) and ³H-citalopram (86.8 Ci/mmol) is purchased from DuPont-NewEngland Nuclear (Boston, Mass.). (R)-(−)-Cocaine hydrochloride for thepharmacological studies was donated by the National Institute on DrugAbuse (NIDA). Fluoxetine was donated by E. Lilly & Co. HPLC analyses arecarried out on a Waters 510 system with detection at 254 nm on aChiralcel OC column (f low rate: 1 mL/min).

EXAMPLE 1 (1R, 1S) -2-Carbomethoxy-8-oxabicyclo(3.2.1)octanone

To 2,5-dimethoxytetrahydrofuran (39.6 g, 0.3 mol) in CH₂Cl₂ (anhydrous,200 mL) at −78° C. under nitrogen was added TiCl₄ (66 mL, 0.6 mol).After stirring for 30 min,1,3-bis(trimethyl-siloxy)-1-methoxybuta-1,3-diene, 2, (Chan, T.-H. andP. Brownbridge (1980), J. Am. Chem. Soc. 102: 3534-3538; Danishefsky, S.and T. Kitahara (1974), J. Am. Chem. Soc. 96: 7807-7808) (78 g, 0.3 mol)in CH₂Cl₂ (anhydrous, 400 mL) was added at a rate such that the internaltemperature was maintained below −55° C. The mixture was stirred for 3h. Saturated NaHCO₃ was added until the mixture was neutral to pH paper.The aqueous layer was extracted with ether (3×1 L). The dried (MgSO₄)combined organic layers were concentrated on a rotavaporator. Theresidue was purified by flash chromatography (20% EtOAc/hexanes) toafford 20.5 g (37%) of 3 as a light brown oil.

EXAMPLE 2(1R,1S)-2-Carbomethoxy-3-{((trifluoromethyl)-sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene

Sodium bistrimethylsilylamide (1.0 M solution in THF, 45 mL) was addeddropwise to 2-carbomethoxy-8-oxabicyclo(3.2.1) octanone, 3,(Brownbridge, P. and T.-H. Chan (1979), Tet. Lett. 46: 4437-4440) (7.12g, 38.65 mmol) in THF (100 mL) at −70° C. under nitrogen. After stirringfor 30 min, N-phenyltrifluoro-methanesulfonimide (15.19 g, 42.52 mmol)was added as a solid at −70° C. The reaction was allowed to warm to roomtemperature and was then stirred overnight. The volatiles were removedon rotavaporator. The residue was dissolved in CH₂Cl₂ (200 mL) andwashed with H₂O (100 mL) and brine (100 mL). The dried (MgSO₄) CH₂Cl₂layer was concentrated to dryness on rotavaporator. The residue waspurified by flash chromatography (10% EtOAc/hexanes) to afford 9.62 g(79%) of 4 as a pale yellow oil.

¹H NMR (CDCl₃, 100MHz): δ5.05 (bm, 1 H),4.70 (t, 1H), 3.83 (s, 3H), 3.0(dd, 1H), 2.0-2.35 (m, 5H).

EXAMPLE 3 (1R,1S)-2-Carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene

2-Carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene(2.0 g, 6.32 mmol), phenyl boronic acid (1.02 g, 8.36 mmol),diethoxymethane (20 mL), LiCl (578 mg, 13.6 mmol),tris(dibenzylideneacetone)dipalladium(0) (247 mg, 0.25 mmol) and Na₂CO₃(2 M solution, 6.1 mL) were combined and heated at reflux for 1 h. Themixture was cooled to room temperature, filtered through celite andwashed with ether (100 mL). The mixture was basified with NH₄OH andwashed with brine. The dried (MgSO₄) ether layer was concentrated todryness. The residue was purified by flash chromatography (10%EtOAc/hexanes) to afford 1.28 g (82%) of(1R,1S)-2-Carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene as a lightbrown viscous oil.

¹H NMR (CDCl₃, 100 MHz): δ7.1-7.5 (m, 5H), 5.00 (bm, 1H), 4.64 (bt, 1H),3.52 (s, 3H), 2.95 (dd, 1H), 1.7-2.2 (m, 5H)

EXAMPLE 4(1R,1S)-2-Carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene

Reaction of2-carbomethoxy-3-{((trifluoromethyl)-sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene(1.87 g, 5.9 mmol), 4-fluorophenyl boronic acid (1.09 g, 7.8 mmol),diethoxymethane (20 mL), LiCl (535 mg, 12.6 mmol),tris(dibenzylideneacetone)-dipalladium(0) (230 mg, 0.25 mmol) and Na₂CO₃(2 M solution, 5.7 mL), as described above, gave 1.36 g (88%) of(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octeneas a light brown viscous oil.

¹H NMR (CDCl₃, 100 MHz): δ7.0-7.2 (m, 4H), 5.00 (bm, 2H), 4.64 (bt, 1H),3.52 (s, 3H), 2.95 (dd, 1H), 1.7-2.2 (m, 5H).

EXAMPLE 5(1R,1S)-2-Carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene

Reaction of 2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene (1.0 g, 3.16 mmol),4-chlorophenyl boronic acid (653 mg, 4.17 mmol), diethoxymethane (10mL), LiCl (286 mg, 6.75 mmol), tris(dibenzylideneacetone)dipalladium(0)(123 mg, 0.13 mmol) and Na₂CO₃ (2M solution, 3.0 mL), as describedabove, gave 0.81 g (92%) of(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octeneas a light brown viscous oil.

¹H NMR (CDCl₃, 100 MHz): δ7.0-7.4 (m, 4H), 5.00 (bm, 1H), 4.64 (bt, 1H),3.52 (s, 3H), 2.95 (dd, 1H), 1.7-2.2 (m, 5H).

EXAMPLE 6(1R,1S)-2-Carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene.

Reaction of2-carbomethoxy-3-{((trifluoromethyl)-sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene(1.0 g, 3.16 mmol), 3,4.-dichlorophenyl boronic acid (796 mg, 4.17mmol), diethoxymethane (10 mL), LiCl (286 mg, 6.75 mmol),tris(dibenzylidene-acetone)-dipalladium(O) (123 mg, 0.13 mmol) andNa₂CO₃ (2 M solution, 3.0 mL), as described above, gave 0.96 g (97%) of(1R,1S)-2-Carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octeneas a light brown viscous oil.

¹H NMR (CDCl₃, 100 MHz): δ6.9-7.5 (m, 3H), 5.00 (bm, 1H), 4.64 (bt, 1H),3.52 (s, 3H), 2.95 (dd, 1H), 1.7-2.2 (m, 5H).

EXAMPLE 7 (1R,1S)-2β-Carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octaneand (1R,1S)-2β-Carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane

To 2-carbomethoxy-3-phenyl-8-oxabicyclo (3.2.1)-2-octene (1.17 g, 4.8mmol) in THF (10 mL) at −70° C. under N₂ was added SmI₂ (0.1 M in THF,215 mL, 21.5 mmol). After the mixture was stirred for 30 min, MeOH(anhydrous, 25 mL) was added. The mixture was stirred at −70° C. for afurther 2 h. The mixture was quenched with TFA (5 mL) and H₂O (100 mL).After warming to 0° C., NH₄OH was added to attain a pH 11 and themixture was then stirred for 30 min. The mixture was filtered throughcelite and washed with ether (400 mL) and then saturated with Na₂S₂O₃.The ether layer was washed with brine. The dried (MgSO₄) ether layer wasconcentrated to dryness. The isomers were separated by gravity columnchromatography (10% EtOAc/hexanes) to afford 789 mg (67%) of(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane as a whitesolid, mp. 96.5-98° C.; and 270 mg (23%) of(1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane as a whitesolid, mp.102.5-104° C.

¹H NMR (CDCl₃, 100 MHz)((1R,1S)-2β-Carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane): δ7.25(bs, 5H), 4.65 (m, 2H), 3.48 (s, 3H), 3.25 (dt, 1H), 2.6-3.0 (m, 2H),1.5-2.3 (m, 5H). Elemental analysis calc. for C₁₅H₁₈O₃: C, 73.14 H,7.37; Found C, 73.07, H, 7.40.

¹H NMR (CDCl₃, 100 MHz)((1R,1S)-2β-Carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane): δ7.25(bs, 5H), 4.51 (bm, 2H), 3.58 (s, 3H), 3.25 (dt, 1H), 2.51 (dd, 1H),2.38 (m, 1H), 1.6-2.2 (m, 4H), 1.41 (ddd, 1H). Elemental analysis calc.for C₁₅H₁₈O₃: C, 73.14, H, 7.37; Found C, 73.02, H, 7.41.

EXAMPLE 8(1R,1S)-2β-Carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octaneand(1R,1S)-2β-Carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane.

Reaction of2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene (1.33 g,5.07 mmol) in THF (10 mL) and SmI₂ (0.1 M in THF, 230 mL, 23.0 mmol), asdescribed above, gave 834 mg (62%) of(1R,1S)-2β-Carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane asa white solid, mp. 58-60° C.; and 300 mg (22%) of(1R,1S)-2β-Carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane asa white solid, mp. 118-120.5° C.

¹H NMR (CDCl₃, 400 MHz)((1R,1S)-2β-Carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane):δ6.9-7.2 (m, 4H), 4.65 (bm, 2H), 3.48 (s, 3H), 3.17 (dt, 1H), 2.78 (d,1H), 2.73 (dt, 1H), 2.13 (m, 1H), 2.05 (m, 1H), 1.90 (m, 1H), 1.78 (m,1H), 1.59 (m, 1H). Elemental analysis calc. for C₁₅H₁₇O₃F: C, 68.16, H,6.48; Found C, 67.88, H, 6.44.

¹H NMR (CDCl₃, 400 MHz)((1R,1S)-2β-Carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane):δ6.9-7.2 (m, 4H), 4.48 (bm, 2H), 3.58 (s, 3H), 3.20 (dt, 1H), 2.44 (dd,1H), 2.38 (m, 1H), 2.12 (m, 1H), 2.00 (m, 1H), 1.75 (m, 1H),1.63 (m,1H), 1.32 (ddd, 1H). Elemental analysis calc. for C₁₅H₁₇O₃F: C, 68.16,H, 6.48; Found C, 68.10, H, 6.52.

EXAMPLE 9(1R,1S)-2β-Carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octaneand (1R,1S)-2β-Carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane

Reaction of2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene (808 mg,2.9 mmol) in THF (8 mL) and SmI₂ (0.1 M in THF, 130 mL, 13.0 mmol), asdescribed above, gave 418 mg (51%) of(1R,1S)-2β-Carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo (3.2.1) octaneas a white solid, mp. 89-90° C.; and 152 mg (19%) of(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane asa white solid, mp. 116-117° C.

¹H NMR (CDCl₃, 100 MHz)((1R,1S)-2β-Carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane):δ7.1-7.4 (m, 4H), 4.65 (m, 2H), 3.48 (s, 3H), 3.20 (dt, 1H), 2.6-2.9 (m,2H), 1.5-2.3 (m, 5H). Elemental analysis calc. for C₁₅H₁₇O₃Cl: C, 64.17,H, 6.10, Cl, 12.63; Found C, 64.01 H, 6.09, Cl, 12.51.

¹H NMR (CDCl₃, 100 MHz)((1R,1S)-2β-Carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo (3.2.1)octane): δ7.1-7.3 (m, 4H), 4.51 (bm, 2H), 3.58 (s, 3H), 3.25 (dt, 1H);2.51 (dd, 1H), 2.38 (m, 1H), 1.6-2.2 (m, 4H), 1.35 (ddd, 1H). Elementalanalysis calc. for C₁₅H₁₇O₃Cl: C, 64.17, H, 6.10, Cl, 12.63; Found C,64.29 H, 6.12, Cl, 12.54.

EXAMPLE 10(1R,1S)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octaneand(1R,1S)-2β-Carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane

Reaction of2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene (829mg, 2.65 mmol) in THF (5 mL) and SmI₂ (0.1 M in THF, 119 mL, 11.9 mmol),as described above, gave 455 mg (55%) of(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octaneas a white solid, mp. 88.5-90° C.; and 115 mg (14%) of(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octaneas a white solid, mp. 132-133.5° C.

¹H NMR (CDCl₃, 100 MHz)((1R,1S)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane):δ7.0-7.5 (m, 3H), 4.65 (bm, 2H), 3.55 (s, 3H), 3.20 (dt, 1H), 2.6-2.9(m, 2H), 1.5-2.3 (m, 5H).

¹H NMR (CDCl₃, 100 MHz)((1R,1S)-2β-Carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane):δ7.0-7.5 (m, 3H), 4.51 (bm, 2H), 3.60 (s, 3H), 3.20 (dt, 1H), 2.51 (dd,1H), 1.6-2.6 (m, 5H), 1.30 (ddd, 1H)

EXAMPLE 11 2-Carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene

Reaction of2-carbomethoxy-3-{((trifluoromethyl)-sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene(1.0 g, 3.16 mmol), 4-bromophenyl boronic acid (1.0 g, 4.98 mmol),diethoxymethane (10 mL), LiCl (286 mg, 6.75 mmol),tris(dibenzylideneacetone)-dipalladium(0) (123 mg, 0.134 mmol) andNa₂CO₃ (2 M solution, 3.0 mL), as described above, gave 416 mg (41%) of2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene as a clearviscous oil.

¹H NMR (CDCl₃, 100 MHz): δ6.9-7.6 (q, 4H), 5.00 (bm, 1H), 4.64 (t, 1H),3.52 (s, 3H), 2.95 (dd, 1H), 1.65-2.4 (m, 5H)

EXAMPLE 122-Carbomethoxy-3-(4-tributyltiphenyl)-8-oxabicyclo(3.2.1)-2-octene

2-Carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo{3.2.1}-2-octene (200 mg,0.62 mmol), bis(tributyltin) (0.74 mL, 1.46 mmol) andtetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) in toluene(4 mL) was degassed by bubbling N₂ through the solution for 10 min. Themixture was then heated at reflux for 6 h. Methylene chloride (10 mL)was added and filtered through celite. The filtrate was concentrated todryness. The residue was purified by flash chromatography andpreparative TLC to afford 206 mg (62%) of2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene as aclear viscous oil.

¹H NMR (CDCl₃, 100 MHz): δ7.0-7.5 (q, 4H), 5.00 (bm, 1H), 4.65 (t, 1H),3.50 (s, 3H), 2.98 (dd, 1H), 0.7-2.3 (m, 32H).

EXAMPLE 13 2-Carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene

2-Carbomethoxy-3-(4-tributyltnphenyl)-8-oxabicyclo(3.2.1)-2-octene (206mg, 0.39 mmol) in THF (anhydrous, 5 mL) was degassed by bubbling N₂ for10 min. N-Iodo-succinimide (96 mg, 0.43 mmol) was added. The reactionmixture was stirred at room temperature for 1 h and concentrated todryness. The residue was dissolved in ether (10 mL), washed withsaturated NaHCO₃ and brine. The dried (MgSO₄) ether layer wasconcentrated to dryness. The residue was purified by flashchromatography and preparative TLC to afford 128 mg (90%) of2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene as a paleyellow viscous oil.

¹H NMR (CDCl₃, 100 MHz): δ6.75-7.80 (q, 4H), 5.00 (bm, 1H) 4.64 (t, 1H),3.54 (s, 3H), 2.95 (dd, 1H), 1.55-2.40 (m, 5H).

EXAMPLE 14 2β-Carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octaneand 2β-Carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane

Reaction of2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene (173 mg,0.54 mmol) in THF (3 mL) and SmI₂ (0.1 M solution in THF, 24 mL,2.4mmol), as described above, gave 81 mg (47%) of2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane as a whitesolid, mp.96-98° C. and 56 mg (32%) of2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)-octane as a whitesolid, mp. 113-115° C.

¹H NMR (CDCl₃, 0 MHz)(2β-Cabomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane): δ7.0-7.6(q, 4H), 4.50 (bd, 2H), 3.60 (s, 3H), 3.25 (dt, 1H), 1.1-2.6 (m, 7H).

¹H NMR (CDCl₃, 100 MHz)(2β-Carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane): δ7.0-7.6(m, 4H), 4.70 (m, 2H),3.53 m1(s, 3H), 3.20 (dt, 1H), 2.55-2.92 (m, 2H),1.5-2.3 (m, 5H).

EXAMPLE 152β-Carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane

2β-Carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane (220 mg,0.68 mmol), bis(tributyltin) (0.8 mL,)tetrakis-(triphenylphosphine)palladium(0) (26 mg) and toluene (3 mL)were combined and degassed for 10 min. The reaction mixture was heatedat reflux for 2 h. CH₂Cl₂ (10 mL) was added and filtered through celite.The filtrate was concentrated to dryness. The residue was purified byflash chromatography and preparative TLC to afford 147 mg (41%) of2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane asclear viscous oil.

¹H NMR(CDCl₃, 100 MHz): δ7.1-7.5 (q, 4H), 4.35-4.65 (bd, 2H), 3.60 (s,3H), 3.25 (dt, 1H), 0.7-2.65 (m, 34H).

EXAMPLE 16 2β-Carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane

2β-Carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane (147mg, 0.275 mmol) and THF (3 mL) was degassed for 10 min.N-Iodosuccinimide (63 mg, 0.28 mmol) was added. The reaction mixture wasstirred at room temperature for 30 min. After concentration to dryness,the residue was dissolved in ether (50 mL) and washed with saturatedNaHCO₃, H₂O and brine. The dry (Na₂SO₄) ether layer was concentrated todryness. The residue was purified by flash chromatography to afford 87mg (85%) of 2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octaneas a white solid, mp. 124-126° C.

¹H NMR (CDCl₃, 100 MHz): δ6.8-7.7 (q, 4H), 4.3-4.7 (bd, 2H), 3.6 (s,3H), 3.2 (dt, 1H), 1.1-2.6 (m, 7H).

EXAMPLE 17 2β-Carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane

To 2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane (112 mg, 0.45mmol) in CH₃CN (anhydrous, 5 mL) at −5° C. was added NO₂BF₄ (83 mg, 0.63mmol). The reaction mixture was stirred at −5° C. for 3 h. A smallamount of ice was added and stirred at −25° C. of 15 min. The CH₃CN wasremoved, the melted ice was extracted with ether. The combined etherextract and CH₃CN solution was concentrated to dryness. The residue wasdissolved in ether (50 mL), washed with saturated NaHCO₃ and brine. Thedried (MgSO₄) ether layer was concentrated to dryness. The residue waspurified by flash chromatography to afford 75.6 mg (57%) of2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane.

¹H NMR (CDCl₃, 100 MHz) δ7.35-8.3 (q, 4H), 4.75 (bt, 2H), 3.54 (s, 3H),3.3 (m, 1H), 2.6-3.0 (m, 2H), 1.7-2.4 (m, 5H).

EXAMPLE 18 2β-Carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane

2β-Carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane (75.6 mg,0.026 mmol) in MeOH (20 mL) was hydrogenated overnight at roomtemperature using Raney Ni as catalyst. The reaction mixture wasfiltered through celite, washed with MeOH and concentrated to dryness.The residue was purified by flash chromatography to afford 43 mg (75%)of 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane.

¹H NMR (CDCl₃, 100 MHz) δ6.5-7.2 (q, 4H), 4.65 (bd, 2H), 3.58 (s, 1H),3.50 (s, 3H), 3.1 (m, 1H), 2.5-2.9 (m, 2H), 1.42-2.32 (m, 6H).

EXAMPLE 19 2β-Carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo (3.2.1)octane

To 2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane (26 mg,0.099 mmol) in CH₂I₂ (2 mL) under N₂ was added isoamylnitrite (0.17 mL,0.126 mmol). The reaction mixture was stirred at room temperature for 1h then at 55° C. for 3 h. CH₂I₂ was removed under reduced pressure. Theresidue was purified by flashed chromatography to afford 15 mg (41%) of2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane as a whitesolid, mp 119-120.5° C.

¹H NMR (CDCl₃, 100 MHz) δ6.90-7.80 (q, 4H), 4.65 (bd, 2H), 3.52 (s, 3H),3.0-3.3 (m 1H), 2.5-2.9 (m, 2H), 1.6-2.3 (m, 5H).

EXAMPLE 20 2-Carbomethoxy-3-hydroxy-8-oxabicyclo(3.2.1)octane

NaBH₄ (2.56 g, 67.7 mmol) was added to a solution of2-carbomethoxy-8-oxabicyclo(3.2.1)octan-3-one, 3, (5.12 g, 27.8 mmol) inMeOH (100 mL) at −78° C. The reaction mixture was left at roomtemperature overnight. The solution was concentrated to dryness. Theresidue was dissolved in water (50 mL), and extracted with CH₂Cl₂ (100,2×50 mL). The combined dried (MgSO₄) extracts were concentrated todryness (yield: 3.9 g). By repeated flash column chromatography fourisomers were obtained from the residue (2.9 g). The major isomer was2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (1.0 g, 26%). Someof the other isomers were isolated to be used in the following reactionsbut there were still mixed fractions. Other pure isomers obtained:

2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (28 mg),

2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane (305 mg) and

2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane (84 mg).

¹H NMR (CDCl₃, 100 MHz)

(2β,3α) δ4.75 (bd, 1H), 4.4 (bt, 2H), 3.75 (s, 3H), 2.55 (s, 1H),1.8-2.5 (m, 7H)

(2β,3β) δ4.8 (bd, 1H), 4.45 (bs, 1H), 3.8-4.15 (m, 1H), 3.78 (s, 3H),2.8 (d, 1H), 1.6-2.1 (m, 7H)

(2α,3α) δ4.65 (bq, 1H), 4.4 (bs, 2H), 3.78 (s, 3H), 3.45 (s, 1H), 2.95(t, 1H), 1.8-2.4 (m, 6H)

(2α,3β) δ4.62 (bq, 1H), 4.5 (bs, 1H), 4.2 (dt,1H), 3.75 (s, 3H), 2.68(dd, 2H), 1.5-2.1 (m, 6H)

EXAMPLE 21 2β-Carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane

2α-Carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (397 mg, 2.1 mmol)and saturated NaHCO₃ (10 mL) were combined and heated overnight atreflux. Water was removed. Methanolic HCl (10 mL) was added and stirredat room temperature overnight. The reaction mixture was concentrated todryness. CH₂Cl₂ (25 mL) was added to the residue. The dried (K₂CO₃)CH₂Cl₂ solution was concentrated to dryness. The residue waschromatographed with silica gel (30% EtOAc/hexanes) to afford 82 mg(21%) of 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane.

¹H NMR (CDCl₃, 100 MHz): δ4.75 (bd, 1H), 4.4 (bt, 2H), 3.75 (s, 3H),2.55 (s, 1H), 1.8-2.5 (m, 7H).

EXAMPLE 222β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane

2β-Carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (103 mg, 0.55mmol), 4,4′-difluorobenzhydrol (244 mg, 1.1 mmol), p-toluenesulfonicacid monohydrate (60 mg, 0.31 mmol) and benzene (50 mL) in a 100 mLround bottom flask fitted with Dean-Stark trap and condenser was heatedovernight at reflux . The reaction mixture was cooled to roomtemperature and basified with NH₄OH. EtOAc (25 mL) was added and washedwith brine. The dried (MgSO₄) organic layer was concentrated to dryness.The residue was purified by flash chromatography to afford 200 mg (93%)2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo-(3.2.1)octaneas a white solid, mp. 92-93° C.

¹H NMR (CDCl₃, 100 MHz) δ6.9-7.5 (m, 8H), 5.38 (s, 1H), 4.75 (bd, 1H),4.4 (bt, 1H), 4.05 (bd, 1H), 3.70 (s, 3H) 2.65 (s, 1H), 1.6-2.5 (m, 6H).

EXAMPLE 232β-Carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane

Reaction of 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo-(3.2.1)octane (103mg, 0.55 mmol), 4,4′-difluoro-benzhydrol (244 mg, 1.1 mmol),p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmol) and benzene (50mL) as above gave 127 mg (59%) of2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo-(3.2.1)octaneas a white solid mp 149-151° C.

¹H NMR (CDCl₃, 100 MHz) δ6.85-7.40 (m, 8H), 5.45 (s, 1H), 4.55 (bd, 2H),3.80 (m, 1H), 3.68 (s, 3H), 2.82 (d, 1H), 2.45 (td, 1H), 1.4-2.1 (m,5H).

EXAMPLE 242α-Carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane

Reaction of 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (110mg, 0.59 mmol), 4,4′-difluoro-benzhydrol (260 mg, 1.18 mmol),p-toluenesulfonic acid monohydrate (171 mg, 0.89 mmol) and benzene (50mL), as above, gave 105 mg (46%) of2α-carbomethoxy-3α-{bis(4-fluorophenyl)-methoxy}-8-oxabicyclo(3.2.1)octaneas a light brown gum.

¹H NMR (CDCl₃, 100 MHz) δ6.8-7.4 (m, 8H), 5.35 (s, 1H), 4.55 (m, 1H),4.30 (bs, 1H), 4.15 (bs, 1H), 3.50 (s, 3H), 2.97 (t, 1H), 2.68 (q, 1H),1.6-2.3 (m, 5H).

EXAMPLE 25 2α-Carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1) octane

Reaction of 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo-(3.2.1)octane (84mg, 0.45 mmol), 4,4′-difluoro-benzhydrol (199 mg, 0.9 mmol),p-toluenesulfonic acid monohydrate (130 mg, 0.68 mmol) and benzene (50mL), as above, gave 99 mg (57%) of2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo-(3.2.1)octaneas a pale yellow gum.

¹H NMR (CDCl₃, 100 MHz) δ6.85-7.40 (m, 8H), 5.50 (s, 1H), 4.40 (m, 2H),4.05 (dt, 1H), 3.68 (s, 3H), 2.91 (dd, 1H), 1.40-2.10 (m, 6H).

EXAMPLE 262-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)oct-3-ene

2-Carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1.]oct-2-ene (285mg, 0.91 mmol), THF/MeOH/H₂O (2 mL/0.67 mL/0.67 ml) and LiOH (139 mg,3.23 mmol) were combined and stirred overnight at room temperature.Water (20 mL) and ether (10 mL) were added to the reaction mixture. Theaqueous layer was acidified with 1N HCl and extracted with ether. Theether layer was washed with brine. The dried (MgSO₄) ether layer wasconcentrated to dryness. The residue was purified by flashchromatography (50 EtOAc/hexane+1% formic acid) to afford 95 mg of the3-ene-acid (used with no further purification).

3-Ene-acid from above (95 mg, 0.32 mmol), MeOH (10 mL) and thionylchloride (10 drops) were combined and stirred overnight at roomtemperature. The reaction mixture was concentrated to dryness. Theresidue was purified by flash chromatography (10-20% EtOAc/hexanes) toafford 94 mg of2-carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicyclo[3.2.1.]oct-3-ene as awhite solid: mp 127-128° C. R_(f) 0.26 (30% EtOAc/hexanes). ¹H NMR(CDCl₃, 100 MHz) 7.1-7.5 (m, 3H), 6.4 (d, 1H), 4.8-5.1 (bd, 1H), 4.6-4.8(bt, 1H), 3.65 (s, 3H), 3.2 (s, 1H), 1.6-2.5 (m, 4H)

EXAMPLE 276(7)-Hydroxy-2-methoxycarbonyl-8-azabicyclo-(3.2.1)octane-2-one; and6(7)-methoxy-2-methoxycarbonyl-8-azabicyclo-(3.2.1)octane-2-one

To a solution of 60 ml of acetic acid and 43 ml of acetic anhydride at0° C., was added slowly 40 g (0.27 mol) of acetone-dicarboxylic acid.The mixture was stirred and the temperature was not allowed to riseabove 10° C. The acid was dissolved slowly and a pale yellow precipitateformed. After 3 h the product was filtered, washed with 30 ml of glacialacetic acid and 100 ml of benzene. The white powder obtained was driedat high vacuum to afford 30 g of acetonedicarboxylic acid anhydride(yield 86%). Mp 137-138° C.

To a flask containing 50 g (0.39 mol) of acetone-dicarboxylic acidanhydride was added 160 ml of cold dry MeOH. The monomethylestersolution was allowed to stand for 1 h and filtered. The filtrate ofacetonedicarboxylic acid monomethyl ester was used directly in thefollowing condensation reaction.

To a 3 L flask with 53.6 g (0.41 mol) of 2,5-dimethoxy-dihydrofuran wasadded 1000 ml of 3N HCl solution. The mixture was left to stand for 12 hat room temperature and then neutralized with ice-cold NaOH solution(equal moles) at 0° C. To this red solution, was added 41.3 g (0.62 mol)of methylamine hydrochloride in 300 ml H₂O, the preformed methanolsolution of the monomethylester (50 g (0.39 mol) of acetone dicarboxylicacid anhydride in 160 ml of methanol) and 50 g of sodium acetate in 200mL of H₂O. The mixture (pH 4.5) was stirred for 2 days and the aciditydecreased to pH 4.9. The red solution was extracted with hexane (450ml×2) to remove nonpolar by-products. The aqueous solution was basifiedfirst with NaOH (1N) to neutral pH, then with potassium carbonate.Sodium chloride (about 200 g) was added. The saturated solution wasextracted with CH₂Cl₂ (250 ml×8), then with a mixed solvent(t-butyl:1,2-dichloroethane, 37:63, 250 ml×8). The CH₂Cl₂ extracted wasdried over K₂CO₃ and solvent was removed to provide 19.6 g of a crudemixture which was separated by column chromatography (SiO₂, 10% Et₃N,30-90% EtOAc in hexane and 10% methanol in EtOAc) to afford 7.5 g of6(7)-methoxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-2-one as an oiland 7 g of6(7)-hydroxy-2-methoxycarbonyl-8-azabicyclo-(3.2.1)octane-2-one as acrystalline solid.

The mixed solvent extracts were dried and removed in vacuo to afford apale yellow solid 19.2 g:6(7)-hydroxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-2-one. Thehydroxy tropanones were used without further purification.

¹H NMR (CDCl₃, 100 MHz): 4.05 (m, 2H, −H), 3.7 (2s, 6H, OCH₃), 3.85 (m,1H), 3.65(1H), 3.45(2H), 3.2(1H), 2.45 (6H), 2.8-1.0(m, 10H).

7-Methoxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-2-one.

¹H NMR (CDCl₃, 100MHz): 12-11.5 (bs, 1H), 3.9 (s, 2H), 3.8 (2s, 6H),3.67 (s, 2H), 3.65-3.2 (m, 4H), 3.34 (2S, 6H), 2.8-2.6 (m, 4H),2.82-2.6(m, 4H), 2.4 (s, 6H), 2.25-1.5 (m, 6H). enol:keto (1:1).

EXAMPLE 286(7)-Methoxymethoxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-2-ones

To a solution of6(7)-hydroxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-2-one (18 g,84.5 mmol) in 200 ml of CH₂Cl₂, 70 ml of dimethoxymethane was added,followed by (18 g, 93 mmol) of p-toluene sulfonic acid monohydrate. Theround-bottom flask was fitted with a soxhlet extractor containing 3-4 Amolecular sieves. The reaction mixture was heated to reflux withstirring until the starting material had disappeared (TLC). The mixturewas cooled and treated with sat. sodium bicarbonate solution andextracted with CH₂Cl₂. The combined organics were dried over K₂CO₃removed in vacuo and applied to column (silica gel, 10% Et₃N, 30%EtOAc/hexane).6-Methoxymethoxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-2-one (2.2g) was obtained as a yellow oil. R_(f) 0.3 (10% Et3N, 30% EtOAc inhexane).

¹H NMR (CDCl₃, 100 MHz): 11.7 (s), 4.64 (2s), 3.76(s), 3.74(s), 3.36(s),3.35(s), 2.69(s), 2.62(s), 2.41 (s), 4.1-1.8 (m). Enol:keto (1:2).

4.34 g of7-Methoxymethoxy-2-methoxycarbonyl-8-azabicyclo-(3.2.1)octane-2-one wasobtained as a yellow oil. R_(f) 0.38 (10% Et₃N, 30% EtOAc in hexane).

¹H NMR (CDCl₃, 100 MHz): 11.75 (s), 4.67-4.58 (m), 3.81 (S), 3.79(s),3.39 (s), 3.37 (s), 2.66 (s), 2.60 (s), 2.42 (s), 4.1-1.8 (m).

A mixture of the (3.2.1)octane-2-ones (2.37 g) and starting material(4.8 g) were obtained from chromatography. Yield 56% based on recoveredstarting material.

EXAMPLE 292-Carbomethoxy-3-trifluoromethylsulfonyloxy-7-methoxymethoxy-8-azabicyclo(3.2.1)-2-octene

To a solution of 2-carbomethoxy-7-methoxymethoxy-8-azabicyclo(3.2.1)octanone (4.25 g, 16.5 mmol) in THF (150 mL), sodiumbistrimethylsilylamide (1.0M solution in THF, 25 mL) was added dropwiseat −70° C. under nitrogen. After stirring for 30 min,N-phenyltrifluoromethanesulfonimide (7.06 g, 19.8 mmol) was added in oneportion at −70° C. The reaction was allowed to warm up to roomtemperature and was stirred overnight. The volatiles were removed onrotary evaporator. The residue was dissolved in CH₂Cl₂ (200 mL), washedwith H₂O (100 mL) and brine (100 mL). The dried (MgSO₄) CH₂Cl₂ layer wasconcentrated to dryness. The residue was purified by flashchromatography (10% Et₃N, 20% EtOAc/hexanes) to afford 3.63 g (65%) of2-carbomethoxy-3-trifluoromethylsulfonyloxy-7-methoxymethoxy-8-axabicyclo(3.2.1)-2-octeneas a pale yellow oil.

¹H NMR (CDCL₃, 100 MHz): 4.69 (m, 2H), 4.21 (dd, 1H), 4.0 (s, 3H), 3.84(s, 3H), 3.53 (m, 1H), 3.37 (s, 3H), 2.85 (dd, 1H), 2.45 (s, 3H),2.4-1.8 (m, 3H).

¹³C NMR (CDCL₃, 100 MHz): 163.5, 149.5, 124.5, 120.9, 996.1, 95.3, 81.5,64.9, 56.5, 55.6, 55.3, 52.2, 39.9, 33.9, 33.7, 30.5.

HRMS Calc. (M+1): 390.0856; Found 390.0811

EXAMPLE 302-Carbomethoxy-3-(trifluoromethyl)sulfonyloxy-6-methoxymethoxy-8-axabicyclo(3.2.1)-2-octene

The procedure described above in Example 29 was utilized to obtain theproduct (64%).

¹H NMR (CDCL₃, 100 MHz): 4.64 (s, 2H), 4.07 (dd, 1H), 3.81 (s, 3H),3.5-3.30(m, 2H), 3.36 (s, 3H), 2.85 (dd, 1H), 2.44 (s, 3H), 2.4-1.8 (m,3H).

EXAMPLE 312-Carbomethoxy-3-trifluoromethylsulfonyloxy-7-methoxy-8-azabicyclo(3.2.1)-2-octene

To a round bottom flask containing 1.1 g of2-carbomethoxy-7-methoxy-8-azabicyclo(3.2.1)-octane-2-one and 3 ml ofEt₃N in 25 ml of CH₂Cl₂ (anhydrous), 1.22 ml (7.2 mmol) of triflicanhydride was added drop wise at 0° C. The mixture was allowed to warmup to room temperature and was stirred overnight. The solvent wasremoved and NaHCO₃ (sat.) was added. The mixture was extracted byCH₂Cl₂. The organics were combined and dried (K₂CO₃), removed in vacuoand the product separated by column chromatography (SiO₂, 10% Et₃N, 30%EtOAc, 60% hexane).

¹H NMR (CDCl₃, 100 MHz): 4.6 ????

General Procedures for Coupling Reactions

To a round-bottom flask with2-carbomethoxy-3-{[(trifluoromethyl)sulfonyl]oxy}-7-methoxymethoxy-8-oxabicyclo(3.2.1)-2-octene(1 eq), LiCl (2 eq), and tris(dibenzylideneacetone)dipalladium(0) (5%molecular eq) in diethoxymethane (10 mL), and Na₂CO₃ (2M solution, 2eq), was added 3,4-dichlorophenyl boronic acid (1.3 eq). The mixture washeated to reflux until the starting material disappeared (TLC). Themixture was cooled to room temperature, filtered through celite andwashed with ether (100 mL). The mixture was basified with NH₄OH andwashed with brine. The dried (MgSO₄) ether layer was concentrated todryness. The residue was purified by flash chromatography (10% Et₃N, 30%EtOAc, 60% hexane) to afford tropene as a light yellow oil.

EXAMPLE 322-Carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)-2-octene

The above general procedure for coupling reactions provided the productin 80% yield. R_(f) 0.29 (10% Et₃N, 30% EtOAc, 60% hexane).

¹H NMR (CDCl₃, 100 MHz): 7.40(d, 1H), 7.19(d, 1H), 6.93(dd, 1H),4.71(AB, 2H), 4.24 (dd, 1H), 3.91 (s, 1H), 3.56 (s, 3H), 3.48 (b, 1H),3.39 (s, 3H), 2.52 (s, 3H), 2.90-1.5 (m, 4H).

¹³C NMR (CDCl₃, 100 MHz): 168.3, 144.8, 142.0, 133.4, 132.8, 131.3,129.9, 128.2, 127.4, 96.4, 83.2, 66.3, 57.5, 56.5, 52.7, 41.5, 36.0,35.7.

EXAMPLE 332-Carbomethoxy-3-(4-fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)-2-octene

The above general procedure for coupling reactions provided the product.

¹H NMR (CDCl₃, 100 MHz): 6.99-7.12 (m, 4H), 5.00 (bm, 2H), 4.64 (t, 1H),3.52 (s, 3H), 2.95 (dd, 1H), 1.71-2.19 (m, 5H)

EXAMPLE 342-Carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)-2-octene

The above general procedure for coupling reactions provided the productin 76% yield. R_(f) 0.29 (10% Et₃N, 30% EtOAc, 60% hexane).

¹H NMR (CDCl₃, 100 MHz): 7.38(d, 1H), 7.23(d, 1H), 6.94 (dd, 1H), 3.95(s, 1H) 3.87 (dd, 1H), 3.56 (s, 3H), 3.39(s, 3H), 2.70 (dd, 3H), 2.49(t, 3H), 2.40-1.6 (m, 4H).

EXAMPLE 352-Carbomethoxy-3-(4-fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)-2-octene

The above general procedure for coupling reactions provided the productin 70% yield. R_(f) 0.37 (10% Et₃N, 30% EtOAc, 60% hexane).

¹H NMR (CDCl₃, 100 MHz): 7.08-7.0 (m, 4H), 3.94 (bs, 1H), 3.80 (dd, 1H),3.53 (s, 3H), 3.39 (d, 3H), 2.76 (dd, 3H), 2.50 (s, 3H), 2.2-1.6 (m,5H).

General Procedures for SmI₂ reduction reactions

To a THF solution of2-carbomethoxy-3-aryl-6(7)-methoxy-methoxy-8-azabicyclo(3.2.1)-2-octene(1 eq) with anhydrous methanol (20 eq) at −78° C. under N₂ was addedSmI₂ (0.1 M solution in THF, 10 eq). The mixture was stirred at −78° C.for 4 h and then quenched with H₂O (10 mL). After warming to roomtemperature, NaHCO₃ (sat.) was added and the mixture was filteredthrough celite and washed with ether (400 mL). The ether layer waswashed with brine. The dried (MgSO₄) ether layer was concentrated todryness. The isomers were separated by gravity column (2-4%methanol/CH₂Cl₂) to afford the boat and chair isomers.

EXAMPLE 362β-Carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octaneand2β-carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane

The reaction of2-carbomethoxy-3-3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)-2-octene(0.494 g, 1.28 mmol) in THF (10 mL) and SmI₂ (0.1 M solution in THF, 128mL, 12.8 mmol) as described above, gave 196 mg (40%) of2β-carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octaneas an oil, and 114 mg (22%) of2β-carbomethoxy-3β-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octaneas an oil.

¹H NMR (CDCl₃, 100 MHz): 7.25 (bs, 5H), 4.51 (bd, 2H), 3.58 (s, 3H),3.25 (dt, 1H), 2.51 (dd, 1H), 2.38 (m, 1H), 1.6-2.2 (m, 4H), 1.41 (ddd,1H).

¹H NMR (CDCl₃, 100 MHz): 7.25 (bs, 5H), 4.65 (m, 2H), 3.48 (s, 3H), 3.25(dt, 1H), 2.78 (d, 1H), 2.73 (dt, 1H), 1.5-2.3 (m, 5H).

EXAMPLE 372β-Carbomethoxy-3-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane and2β-carbomethoxy-3β-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane

Reaction of2-carbomethoxy-3-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)-2-octene(0.494 g, 1.28 mmol) in THF (10 mL) and SmI₂ (0.1 M solution in THF, 128mL, 12.8 mmol), as described, above gave 196 mg (40%) of2β-carbomethoxy-3-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octaneas an oil, and 114 mg (22%) of2β-carbomethoxy-3β-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octaneas an oil.

¹H NMR (CDCl₃, 100 MHz)(2β-Carbomethoxy-3-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane):7.3-6.8 (m, 4H), 4.65 (2d, 2H), 4.25 (dd, 1H), 3.60 (s, 3H), 3.38 (s,3H), 2.55 (s, 3H), 3.5-1.8 (m, 9H).

¹H NMR (CDCl₃, 100 MHz)(2β-Carbomethoxy-3β-(fluorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane):7.3-6.8 (m, 4H), 4.70 (s, 2H), 4.35 (dd, 1H), 3.59 (bs, 1H), 3.50 (s,3H), 3.42 (s, 3H), 3.0 (m, 1H), 2.6 (m, 1H), 2.48 (s, 3H), 2.5-1.2 (m,5H).

EXAMPLE 382β-Carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octaneand2β-carbomethoxy-3β-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane

Reaction of2-carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)-2-octene(0.287 g, 0.81 mmol) in THF (10 mL) and SmI₂ (0.1 M solution in THF, 81mL, 8.1 mmol) in 5 mL of methanol as described above gave 123.4 mg (43%)of2β-carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octaneas an oil, and 83 mg (32%) of2β-carbomethoxy-3β-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octaneas an oil.

¹H NMR (CDCl₃, 100 MHz)(2β-Carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane):7.25(bs, 5H), 4.51.

¹H NMR (CDCl₃, 400 MHz)(2β-Carbomethoxy-3β-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane):7.31 (d, J=8.5 Hz, 1H, Ph), 7.28 (d, J=1.8 Hz, 1H, Ph), 7.07 (dd, J=8.5,1.8 Hz, 1H, Ph), 3.96 (dd, J=7.3, 3.0 Hz, 1H, H_(7a)), 3.61 (br s, 1H,H₁), 3.52 (br s, 1H, H₅), 3.51 (s, 3H, CO₂Me), 3.34 (s, 3H, OMe), 2.95(dd, J=4.6, 3.7 Hz, 1H, H_(2a)), 2.64 (ddd, J=9.8, 6.4, 4.6 Hz, 1H,H_(3a)), 2.47 (m, 1H, H_(4b)), 2.43 (s, 3H, NMe), 2.18 (ddd, J=14.1,6.7, 3.0 Hz, 1H, H_(6b)), 2.10 (dd, J=14.0, 7.3 Hz, 1H, H_(6a)), 1.55(m, 1H, H_(4a)).

EXAMPLE 392β-Carbomethoxy-3-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane and2β-Carbomethoxy-3β-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane

Reaction of2-carbomethoxy-3-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)-2-octene(0.585 g, 1.92 mmol) in THF (10 mL) and SmI₂ (0.1 M solution in THF, 192mL, 19.2 mmol), as described above, gave 230 mg (40%) of2β-carbomethoxy-3-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane asan oil, and 245 mg (42%) of2β-carbomethoxy-3β-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane asan oil.

¹H NMR (CDCl₃, 100 MHz)(2β-Carbomethoxy-3-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane):7.3-6.8(m, 4H), 3.86 (dd, 1H), 3.61(s, 3H), 3.38(s, 3H), 2.53 (s, 3H),3.5-1.8 (m, 9H).

¹H NMR (CDCl₃, 100 MHz)(2β-Carbomethoxy-3β-(fluorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane):7.3-7.0 (m, 4H), 4.70 (s, 2H), 4.35 (dd, 1H), 3.59 (bs, 1H), 3.50 (s,3H), 3.42 (s, 3H), 3.0 (m, 1H), 2.6 (m, 1H), 2.48 (s, 3H), 2.5-1.2 (m,5H).

General Procedure for the deprotection of the MOM group

To a solution of MOM protected alcohol in CH₂Cl₂ (anhyd.) containing 4 Åmolecular sieves at 0° C., was added TMSBr (10 eq). The solution wasstirred for 1 h at 0° C., then warmed to room temperature. Afterstirring overnight, NaHCO3 (sat) was added and extracted with CH₂Cl₂.The extract was dried (Na₂CO₃) and reduced in vacuo to apply to a column(Silica Gel, 10% Et₃N, 30-90% EtOAc in hexane). The desired product wasobtained as a solid and was dissolved in minimum volume of EtOAc. Tothis solution ethereal HCl (1M, 1.1 eq) was added dropwise to afford theHCl salt.

EXAMPLE 402β-Carbomethoxy-3-(3,4-dichlorophenyl)-7-hydroxy-8-azabicyclo(3.2.1)octane

2β-Carbomethoxy-3-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane(49 mg, 0.13 mmol) and TMSBr (0.17 mL, 1.3 mmol) were reacted, asdescribed above. The product was obtained in 87% yield (41 mg). R_(f)0.18 (10% Et₃N, 40% EtOAc, 50% hexane).

EXAMPLE 412β-Carbomethoxy-3β-(3,4-dichlorophenyl)-7-methoxy-8-azabicyclo(3.2.1)octane

2β-Carbomethoxy-3β-(3,4-dichlorophenyl)-7-methoxymethoxy-8-azabicyclo(3.2.1)octane(50 mg, 0.13 mmol) and TMSBr (0.17 mL, 1.3 mmol) were reacted, asdescribed above. The product was obtained in 88% yield (42.1 mg). R_(f)0.18 (10% Et₃N, 40% EtOAc, 50% hexane).

¹H NMR data (400 MHz, CDCl₃): (7β-OH) 7.31 (d, J=8.5 Hz, 1H, Ph), 7.27(d, J=1.8 Hz, 1H, Ph), 7.05 (dd, J=8.5, 1.8 Hz, 1H, Ph), 4.52 (dd,J=6.8, 3.1 Hz, 1H, H_(7a)), 3.58 (br s,

Biological assays were performed using the following procedures.

A. Tissue sources and preparation.

Brain tissue from adult male and female cynomolgus monkeys (Macacafascicularis) is stored at −85° C. in the primate brain bank at the NewEngland Regional Primate Research Center. The caudate-putamen will bedissected from coronal slices and yields 1.4±0.4 g tissue. Membranes areprepared as described previously. Briefly, the caudate-putamen ishomogenized in 10 volumes (w/v) of ice-cold Tris.HCl buffer (50 mM, pH7.4 at 4° C.) and centrifuged at 38,00×g for 20 min in the cold. Theresulting pellet is suspended in 40 volumes of buffer, and the entireprocedure is repeated twice. The membrane suspension (25 mg original wetweight of tissue/ml) is diluted to 12 ml/ml for ³H-WIN 35,428 or³H-citalopram assay in buffer just before assay and is dispersed with aBrinkmann Polytron homogenizer (setting #5) for 15 sec. All experimentsare conducted in triplicate and each experiment is repeated in each of2-3 preparations from individual brains.

TABLE 3 Elemental Analyses CALCULATED FOUND COMPOUND C H Cl C H Cl(1R,1S)-2-Carbomethoxy-3-phenyl-8- 73.75 6.60 73.72 6.65oxabicyclo(3.2.1)-2-octene Anal. (C₁₅H₁₆O₃)(1R,1S)-2-Carbomethoxy-3-(4-fluorophenyl-) 68.69 5.77 68.55 5.848-oxabicyclo(3.2.1)-2-octene Anal. (C₁₅H₁₅O₃F)(1R,1S)-2-Carbomethoxy-3-(4-chlorophenyl)- 64.63 5.42 12.72 64.56 5.4612.65 8-oxabicyclo(3.2.1)-2-octene Anal. (C₁₅H₁₅O₃Cl)(1R,1S)-2-Carbomethoxy-3-(4-bromophenyl)- 55.74 4.68 Br: 55.46 4.70 Br:8-oxabicyclo(3.2.1)-2-octene 24.72 24.49 Anal. (C₁₅H₁₅O₃Br)(1R,1S)-2-Carbomethoxy-3-(4-iodophenyl)-8- 48.67 4.08 I: 48.91 4.21 I:oxabicyclo(3.2.1)-2-octene 34.28 34.01 Anal. (C₁₅H₁₅O₃I)(1R,1S)-2-Carbomethoxy-3-(3,4- 57.53 4.51 22.64 57.39 4.54 22.50dichlorophenyl)-8-oxabicyclo(3.2.1)-2- octene Anal. (C₁₅H₁₄O₃Cl₂)(1R)-2-Carbomethoxy-3-(3,4- 57.53 4.51 22.64 57.50 4.55 22.71dichlorophenyl)-8-oxabicyclo(3.2.1)-2- octene Anal. (C₁₅H₁₄O₃Cl₂)(1S)-2-Carbomethoxy-3-(3,4- 57.53 4.51 22.64 57.63 4.48 22.54dichlorophenyl)-8-oxabicyclo(3.2.1)-2- octene Anal. (C₁₅H₁₄O₃Cl₂)(1R,1S)-2 -Carbomethoxy-3 -phenyl-8- 73.14 7.37 73.07 7.40oxabicyclo(3.2.1) octane Anal. (C₁₅H₁₈O₃) (1R,1S)-2 -Carbomethoxy-3-phenyl-8- 73.14 7.37 73.02 7.41 oxabicyclo(3.2.1)octane Anal.(C₁₅H₁₈O₃) (1R,1S)-2 -Carbomethoxy-3 (4- 68.16 6.48 67.88 6.44fluorophenyl)-8-oxabicyclo(3.2.1)octane Anal. (C₁₅H₁₇O₃F) (1R,1S)-2-Carbomethoxy-3 (4- 68.16 6.48 68.10 6.52 fluorophenyl)-8-oxabicyclo(3.2.1)octane Anal. (C₁₅H₁₇O₃F) (1R,1S)-2-Carbomethoxy-3 -(4- 64.17 6.1012.63 64.01 6.09 12.51 chlorophenyl)-8-oxabicyclo(3.2.1)octane Anal.(C₁₅H₁₇O₃Cl) (1R,1S)-2 -Carbomethoxy-3 -(4- 64.17 6.10 12.63 64.29 6.1212.54 chlorophenyl)-8-oxabicyclo (3.2.1) octane Anal. (C₁₅H₁₇O₃Cl)(1R,1S)-2- Carbomethoxy-3 (4- 55.40 5.27 Br: 55.30 5.26 24.45bromophenyl)-8-oxabicyclo (3.2.1) octane 24.57 Anal. (C₁₅H₁₇O₃Br)(1R,1S)-2 -Carbomethoxy-3 (4- 55.40 5.27 Br: 55.49 5.29 Br:bromophenyl)-8-oxabicyclo (3.2.1)octane 24.57 24.63 Anal. (C₁₅H₁₇O₃Br)(1R,1S)-2 -Carbomethoxy-3 (4-iodophenyl)- 48.40 4.60 I: 48.55 4.66 I:8-oxabicyclo(3.2.1)octane 34.10 34.00 Anal. (C₁₅H₁₇O₃I) (1R,1S)-2-Carbomethoxy-3 -(3,4- 57.16 5.12 22.50 57.18 5.19 22.61dichlorophenyl)-8-oxabicyclo(3.2.1) octane Anal. (C₁₅H₁₆O₃Cl₂) (1R,1S)-2-Carbomethoxy-3 -(3,4- 57.16 5.12 22.50 57.27 5.08 22.57dichlorophenyl)-8-oxabicyclo(3.2.1)octane Anal. (C₁₅H₁₆O₃Cl₂) (1R)-2-Carbomethoxy-3 -(3,4- 57.16 5.12 22.50 57.08 5.16 22.59dichlorophenyl)-8-oxabicyclo(3.2.1) octane Anal. (C₁₅H₁₆O₃Cl₂) (1R)-2-Carbomethoxy-3 -(3,4- 57.16 5.12 22.50 57.27 5.18 22.57dichlorophenyl)-8-oxabicyclo(3.2.1) octane Anal. (C₁₅H₁₆O₃Cl₂) (1S)-2-Carbomethoxy-3 -(3,4- 57.16 5.12 22.50 57.28 5.16 22.42dichlorophenyl)-8-oxabicyclo(3.2.1) octane Anal. (C₁₅H₁₆O₃Cl₂)(1S)-2-Carbomethoxy-3 -(3,4- 57.16 5.12 22.50 57.07 5.15 22.40dichlorophenyl)-8-oxabicyclo (3.2.1) octane Anal. (C₁₅H₁₆O₃Cl₂)(1R)-2-Carbomethoxy-8- 62.63 6.64 62.72 6.64oxabicyclo(3.2.1)octa-2-ene-3-(1′S)- camphanate Anal. (C₁₉H₂₄O₇)(1S)-2-Carbomethoxy-8- 62.63 6.64 62.72 6.64oxabicyclo(3.2.1)octa-2-ene-3-(1′R)- camphanate Anal. (C₁₉H₂₄O₇)(1R,1S)-2 Carbomethoxy-3 -[bis(4- 68.03 5.71 68.12 5.74fluorophenyl)methoxy]-8-oxabicyclo [3.2.1.]octane Anal. (C₂₂H₂₂O₄F₂)(1R,1S)-2 Carbomethoxy-3 -[bis(4- 68.03 5.71 67.92 5.68fluorophenyl)methoxy]-8-oxabicyclo [3.2.1.]octane Anal. (C₂₂H₂₂O₄F₂)(1R,1S)-2 Carbomethoxy-3 -[bis(4- 67.00 5.79 67.06 5.78fluorophenyl)methoxy]-8-oxabicyclo [3.2.1.]octane Anal. (C₂₂H₂₂O₄F₂ 1/3H₂O) (1R,1S)-2 Carbomethoxy-3 -[bis(4- 68.03 5.71 67.98 5.18fluorophenyl)methoxy]-8-oxabicyclo (3.2.1)octane Anal. (C₂₂H₂₂O₄F₂)2-Carbomethoxy-3-(3,4-dichlorphenyl)-8- 57.53 4.51 22.64 57.58 4.5222.54 oxabicylo(3.2.1)oct-3-ene Anal. (C₁₅H₁₄O₃Cl₂)7-Methoxymethoxy-2-methoxycarbonyl-8- 56.02 7.44 N: 55.99 7.41 N:azabicyclo(3.2.1)octane-2-one 5.44 5.38 Anal. (C₁₂H₁₉NO₅)2-Carbomethoxy-3-(3,4-dichlorophenyl)-7- 55.97 5.48 N: 55.89 5.54 N:methoxymethoxy-8-azabicyclo(3.2.1)-2- 3.63 3.57 octene Anal. (C₁₂H₁₉NO₅)2-Carbomethoxy-3-(3,4-dichlorophenyl)-7- 51.99 5.13 N: 51.86 5.13 N:methoxy-8-azabicyclo(3.2.1)-2-octene 3.57 3.51 Anal. (C₁₇H₁₉ClNO₃ HCl)Cl: Cl: 27.08 27.19 2-Carbomethoxy-3-(4-fluorophenyl)-7- 59.74 6.19 N:59.48 6.23 N: methoxy-8-azabicyclo(3.2.1)-2-octene 4.10 4.08 Anal.(C₁₂H₁₉NO₅) 2 -carbomethoxy-3 -(3,4-dichlorophenyl)-7- 73.14 7.37 73.027.41 methoxymethoxy-8-azabicyclo(3.2.1) octane Anal. (C₁₅H₁₈O₃) 2-carbomethoxy-3 -(3,4-dichlorophenyl)-7- 73.14 7.37 73.07 7.40methoxymethoxy-8-azabicyclo(3.2.1)octane Anal. (C₁₅H₁₈O₃)2-Carbomethoxy-3 -(3,4-dichlorophenyl)-7- 48.41 5.46 N: 48.42 5.29 N:hydroxy-8-azabicyclo(3.2.1)octane 3.53 3.35 Anal. (C₁₆H₂₀Cl₃NO₃ 0.7H₂O)Cl: Cl: 27.69 27.50 2 -Carbomethoxy-3 -(3,4-dichlorophenyl)-7- 48.415.46 N: 48.50 5.41 N: methoxy-8-azabicyclo(3.2.1)octane 3.53 3.35, Anal.(C₁₆H₂₀Cl₃NO₃ 0.7H₂O) Cl: Cl: 27.69 27.50 2 -Carbomethoxy-3-(fluorophenyl)-7- 56.15 6.99 N: 56.04 6.97 N:methoxy-8-azabicyclo(3.2.1)octane 3.85 3.79 Anal. (C₁₇H₂₃ClFNO₃ 0.11H₂O)2 -Carbomethoxy-3 -(fluorophenyl)-7- 56.43 6.96 N: 56.57 6.80 N:methoxy-8-azabicyclo(3.2.1)octane 3.87 3.83 Anal. (C₁₇H₂₃ClFNO₃ 0.1H₂O)2 -Carbomethoxy-3 -(3,4-dichlorophenyl)-7- 56.99 5.91 N: 57.04 5.93 N:methoxy-8-azabicyclo(3.2.1)octane 3.91 3.97, Anal. C₁₇H₂₁NCl₂O₃) Cl: Cl:19.79 19.86 2 -Carbomethoxy-3 -(3,4-dichlorophenyl)-7- 56.99 5.91 N:56.71 5.97 N: methoxy-8-azabicyclo(3.2.1)octane 3.91 3.76, Anal.(C₁₇H₂₁NCl₂O₃) Cl: Cl: 19.79 20.03

B. Dopamine transporter assay.

The dopamine transporter is labeled with ³H-WIN35,428 (70-85 Ci/mmol,DuPont-NEN). The affinity of novel compounds for the dopaminetransporter will be determined in experiments by incubating tissue witha fixed concentration of ³H-WIN35,428 and a range of concentration ofthe compound as previously described {Madras, 1989 #21} Stock solutionsare diluted serially in the assay buffer and added (0.2 mL) to the assaymedium. The assay tubes receive, in Tris.HCl buffer (50 mM, pH 7.4 at0-4° C.; NaCl 100 mM), the following constituents at a final assayconcentration: drug (0.2 ml; 1 pM-300 μM, depending on affinity),³H-WIN35,428 (0.2 ml; 0.3 or 1 nM); membrane preparation (0.2 ml; 1-4 mgoriginal wet weight of tissue/ml), depending on the assay. The 2 hincubation (0-4° C.) is initiated by addition of membranes andterminated by rapid filtration over Whatman GF/B glass fiber filterspre-soaked in 0.1% bovine serum albumin (Sigma Chem. Co.). The filtersare washed twice with 5 ml Tris.HCl buffer (50 mM), incubated overnightat 0-4° C. in scintillation fluor (Beckman Ready-Value, 5 ml) andradioactivity (dpm) is measured by liquid scintillation spectrometry(Beckman 1801). Total binding is defined as ³H-WIN35,428 bound in thepresence of ineffective concentrations of the drug. Non-specific bindingis defined as ³H-WIN35,428 bound in the presence of an excess (30 μM) of(−)-cocaine or mazindol (1 μM). Specific binding is the differencebetween the two values.

C. Serotonin transporter assay.

The serotonin transporter is labeled by ³H-citalopram (spec. act.: 82Ci/mmol, DuPont-NEN). The serotonin transporter is assayed incaudate-putamen membranes using conditions similar to those for thedopamine transporter. The serotonin transporter is expressed atrelatively high density in the caudate-putamen (20 pmol/g) and theaffinity of ³H-citalopram is approximately 2 nM. Drug affinities aredetermined by incubating tissue with a fixed concentration of³H-citalopram and a range of concentrations of the test compounds. Theassay tubes receive, in Tris.HCl buffer (50 mM, pH 7.4 at 0-4° C.; NaCl100 mM), the following constituents at a final assay concentration: drug(0.2 ml of various concentrations); ³H-citalopram (0.2 ml; 1 nM);membrane preparation (0.2 ml; 4 mg original wet weight of tissue/ml).The 2 h incubation (0-4° C.) is initiated by addition of membranes andterminated by rapid filtration over Whatman GF/B glass fiber filterspre-soaked in 0.1% polyethyleneimine. The filters are washed twice with5 ml Tris.HCl buffer (50 mM) and the remaining steps are carried out asdescribed above. Total binding is defined as ³H-citalopram bound in thepresence of ineffective concentrations of unlabeled citalopram (1 pM) orthe test compounds. Non-specific binding is defined as ³H-citaloprambound in the presence of an excess (10 μM) of fluoxetine. Specificbinding is the difference between the two values.

D. Norepinephrine transporter assay.

The selection of thalamus is based on a previous autoradiographic studyreporting this brain region to have high densities of ³H-nisoxetine. Theassay conditions for thalamus membranes (Madras 1996) are similar tothose for the serotonin transporter. The affinity of ³H-nisoxetine(spec. act.: 74 Ci/mmol, DuPont-NEN) for the norepinephrine transporteris determined in experiments by incubating tissue with a fixedconcentration of ³H-nisoxetine and a range of concentrations ofunlabeled nisoxetine. The assay tubes receive the following constituentsat a final assay concentration: nisoxetine or drug (0.2 ml; 1 pM-300μM), ³H-nisoxetine (0.2 ml; 0.6 nM); membrane preparation (0.2ml; 4 mgoriginal wet weight of tissue/ml). The buffer in the assay medium isTris.HCl: 50 mM, pH 7.4 at 0-4° C.; NaCl 300 mM. The 16 h incubation at0-4° C. is initiated by addition of membranes and terminated by rapidfiltration over Whatman GF/B glass fiber filters pre-soaked in 0.1%polyethyleneimine. The remaining steps are described above. Totalbinding is defined as ³H-nisoxetine bound in the presence of ineffectiveconcentrations of drug. Non-specific binding is defined as ³H-nisoxetinebound in the presence of an excess (10 μM) of desipramine. Specificbinding is the difference between the two values.

E. Data Analysis.

Data are analyzed by EBDA and LIGAND computer software(Elsevier-Biosoft, UK) Final estimates of IC₅₀ and nH values arecomputed by the EBDA program. Baseline values for the individual drugsare established by computer analysis using the baseline drugs as guide.The LIGAND program provides final parameter estimates of the novelcompounds by iterative non-linear curve-fitting and evaluation of one-or two-component binding models.

The present invention has been described in detail, including thepreferred embodiments thereof. However, it will be appreciated thatthose skilled in the art, upon consideration of the present disclosure,may make modifications and/or improvements of this invention and stillbe within the scope and spirit of this invention as set forth in thefollowing claims.

We claim:
 1. A compound having the structural formula:

wherein: R₁=COOCH₃, COR₃, lower alkyl, lower alkenyl, lower alkynyl,CONHR₄, or COR₆; R₂=is a 6α, 6β, 7α or 7β substituent, which is selectedfrom OH, OR₃, F, Cl, Br, and NHR₃; X=O, S; SO, SO₂, R₃=H, CH₃, CH₃CH₂,CH₃(CH₂)_(n) (CH₂)_(n)C₆H₄Y, C₆H₄Y, CHCH₂, lower alkyl, lower alkenyl,or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN,NHCOCH₃, N(CH₃)₂, (CH₂)_(n)CH₃, COCH₃, or C(CH₃)₃; R₄=CH₃, CH₂CH₃, orCH₃SO₂; Ar=phenyl-R₅, naphthyl-R₅, anthracenyl-R₅, phenanthrenyl-R₅, ordiphenylmethoxy-R₅; R₅=Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN,NHCOCH₃, N(CH₃)₂, (CH₂)nCH₃, COCH₃, C(CH₃)₃ where n=0-6, 4-F, 4-Cl, 4-I,2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc,3,4-diOCH₃, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, loweralkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(loweralkoxy); R₆=morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5;and when X=O, R₂ can be H.
 2. The compound of claim 1 having thefollowing structural formula:

wherein X, Ar, R₂ and m have the same meaning as defined above.
 3. Thecompound of claim 2, wherein Ar is halogen substituted phenyl or halogensubstituted diarylmethoxy.
 4. The compound of claim 2, wherein Ar is amono- or di-halogen substituted phenyl.
 5. The compound of claim 2,wherein the aryl ring can be substituted with one or more halide atoms,hydroxy groups, nitro groups, amino groups, cyano groups, lower alkylgroups having from 1-8 carbon atoms, lower alkoxy groups having from 1-8carbon atoms, lower alkenyl groups having from 2-8 carbon atoms, orlower alkynyl groups having from 2-8 carbon atoms.
 6. The compound ofclaim 5, wherein the aryl ring can be substituted with chloride oriodide.
 7. The compound of claim 5, wherein the amino group is a mono-or di- alkyl substituted group having from 1-8 carbon atoms.
 8. Thecompound of claim 2, wherein the aryl group has a substituent selectedfrom the group consisting of Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN,NHCOCH₃, N(CH₃)₂, COCH₃, C(CH₃)₃, (CH₂)_(n)CH₃ where n=0-6, allyl,isopropyl and isobutyl.
 9. The compound of claim 2, wherein the arylgroup has a substituent selected from the group consisting of loweralkyl, lower alkenyl and lower alkynyl.
 10. The compound of claim 2,wherein the aryl group is substituted with a member of the groupconsisting of 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl,3,4-diOH, 3,4-diOAc, 3,4-diOCH₃, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH and3-F-4-OH.
 11. The compound of claim 1 having the following structuralformula:

where R is H, 4-F, 4-Cl, 4-Br, 4-I or 4-CH₃.
 12. The compound of claim11, wherein the aryl group is a 3,4 dihalo substituted phenyl.
 13. Thecompound of claim 12, wherein the aryl group is 3,4-diclorophenyl. 14.The compound of claim 1 having the following structural formula:

where X is an oxygen, and R is a lower alkenyl or lower alkynyl grouphaving from about 2 to about 8 carbon atoms.
 15. The compound of claim14 wherein the lower alkenyl or lower alkynyl group is selected from thegroup consisting of ethenyl, propenyl, butenyl, propynyl and butynyl.16. The compound of claim 1 having the following structural formula:

where X is an oxygen atom and Ar is 4-substituted phenyl, naphthyl,anthracenyl or phenanthrenyl.
 17. The compound of claim 1 having thefollowing structural formula:

where X is oxygen, R₁ is morpholinyl, piperidinyl or methoxy, Ar isphenyl, substituted phenyl, naphthyl or substituted naphthyl.
 18. Thecompound of claim 17, wherein Ar is substituted with halogen, loweralkenyl having 2-8 carbon atoms or lower alkynyl having 2-8 carbonatoms.
 19. The compound of claim 17, wherein Ar is substituted with4-Cl, 4-F, 4-Br, 4-I, 3,4-Cl₂, ethenyl, propenyl, butenyl, propynyl orbutynyl.
 20. The compound of claim 1 having the following structuralformula:

where X is O, R₁ is morpholinyl, piperidinyl or methoxy, R₂ is hydroxyor methoxy in the 6- or 7- position, Ar is phenyl or naphthyl either ofwhich can be substituted with halogen, alkenyl having 2-8 carbon atomsor alkynyl having 2-8 carbon atoms.
 21. The compound of claim 20,wherein Ar is substituted with 4-Cl, 4-F, 4-Br, 4-I, 3,4-Cl₂, ethenyl,propenyl, butenyl, propynyl or butynyl.
 22. The compound of claim 1selected from the group consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)-sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;i.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;j.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;k.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;l.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;m.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p.2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q.2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ad.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicylo(3.2.1)octane;ae.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;af.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.23. The compound of claim 1 selected from the group consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; andh. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.
 24. Thecompound of claim 1 selected from the group consisting of: a.(1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;d.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;e.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;f.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;g.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;h.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;u.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;v.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;w.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.25. A method for inhibiting 5-hydroxytryptamine reuptake of a monoaminetransporter comprising contacting the monoamine transporter with acompound having the structural formula:

wherein: R₁=COOCH₃, COR₃, lower alkyl, lower alkenyl, lower alkynyl,CONHR₄, or COR₆; R₂=is a 6α, 6β, 7α or 7β substituent, which can beselected from OH, OR₃, F, Cl, Br, and NHR₃; X=O, S; SO, SO₂, R₃=H, CH₃,CH₃CH₂, CH₃(CH₂)_(n) (CH₂)_(n)C₆H₄Y, C₆H₄Y, CHCH₂, lower alkyl, loweralkenyl or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂,CN, NHCOCH₃, N(CH₃)₂, (CH₂)_(n)CH₃, COCH₃, or C(CH₃)₃; R₄=CH₃, CH₂CH₃,or CH₃SO₂; Ar=phenyl-R₅, naphthyl-R₅, anthracenyl-R₅, phenanthrenyl-R₅,or diphenylmethoxy-R₅; R₅=Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN,NHCOCH₃, N(CH₃)₂, (CH₂)nCH₃, COCH₃, C(CH₃)₃ where n=0-6, 4-F, 4-Cl, 4-I,2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc,3,4-diOCH₃, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, loweralkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(loweralkoxy); R₆=morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5;and when X=O, R₂ can be H.
 26. The method of claim 25, wherein themonoamine transporter is selected from the group consisting of adopamine transporter, a serotonin transporter and a norepinephrinetransporter.
 27. The method of claim 25, wherein the compound isselected from the group consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;i. (1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane; j.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;k.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;l.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;m.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p.2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q.2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ad.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ae.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;af.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.28. The method of claim 25, wherein the compound is selected from thegroup consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene andh. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.
 29. Themethod of claim 25, wherein the compound is selected from the groupconsisting of: a.(1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;d.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;e.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;f.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;g.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;h.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;u.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;v.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;w.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.30. A method for inhibiting 5-hydroxytryptamine reuptake of a monoaminetransporter in a mammal comprising administering to the mammal a5-hydroxytryptamine reuptake inhibiting amount of a compound having thestructural formula:

wherein: R₁=COOCH₃, COR₃, lower alkyl, lower alkenyl, lower alkynyl,CONHR₄, or COR₆; R₂=is a 6α, 6β, 7α or 7β substituent, which can beselected from OH, OR₃, F, Cl, Br, and NHR₃; X=O, S; SO, SO₂; R₃=H, CH₃,CH₃CH₂, CH₃(CH₂)_(n) (CH₂)_(n)C₆H₄Y, C₆H₄Y, CHCH₂, lower alkyl, loweralkenyl or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂,CN, NHCOCH₃, N(CH₃)₂, (CH₂)_(n)CH₃, COCH₃, or C(CH₃)₃; R₄=CH₃, CH₂CH₃,or CH₃SO₂; Ar=phenyl-R₅, naphthyl-R₅, anthracenyl-R₅, phenanthrenyl-R₅,or diphenylmethoxy-R₅; R₅=Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN,NHCOCH₃, N(CH₃)₂, (CH₂)nCH₃, COCH₃, C(CH₃)₃ where n=0-6, 4-F, 4-Cl, 4-I,2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc,3,4-diOCH₃, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, loweralkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(loweralkoxy); R₆=morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5;and when X=O, R₂ can be H.
 31. The method of claim 30, wherein thecompound is selected from the group consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;i.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;j.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;k.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;l.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;m.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p.2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q.2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ad.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ae.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;af.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.32. The method of claim 30, wherein the compound is selected from thegroup consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene andh. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.
 33. Themethod of claim 30, wherein the compound is selected from the groupconsisting of: a.(1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b.(1R,1s)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;d.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;e.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;f.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;g.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;h.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;u.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;v.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;w.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.34. A method for inhibiting dopamine reuptake of a dopamine transporterin a mammal comprising administering to the mammal a dopamine reuptakeinhibiting amount of a compound having the structural formula:

wherein: R₁=COOCH₃, COR₃, lower alkyl, lower alkenyl, lower alkynyl,CONHR₄, or COR₆; R₂=is a 6α, 6β, 7α or 7β substituent, which can beselected from OH, OR₃, F, Cl, Br, and NHR₃; X=O, S; SO, SO₂; R₃=H, CH₃,CH₃CH₂, CH₃(CH₂)_(n) (CH₂)_(n)C₆H₄Y, C₆H₄Y, CHCH₂, lower alkyl, loweralkenyl or lower alkynyl; Y=H, Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂,CN, NHCOCH₃, N(CH₃)₂, (CH₂)_(n)CH₃, COCH₃, or C(CH₃)₃; R₄=CH₃, CH₂CH₃,or CH₃SO₂; Ar=phenyl-R₅, naphthyl-R₅, anthracenyl-R₅, phenanthrenyl-R₅,or diphenylmethoxy-R₅; R₅=Br, Cl, I, F, OH, OCH₃, CF₃, NO₂, NH₂, CN,NHCOCH₃, N(CH₃)₂, (CH₂)nCH₃, COCH₃, C(CH₃)₃ where n=0-6, 4-F, 4-Cl, 4-I,2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc,3,4-diOCH₃, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, loweralkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(loweralkoxy); R₆=morpholinyl or piperidinyl; m=0 or 1; n=0, 1, 2, 3, 4 or 5;and when X=O, R₂ can be H.
 35. The method of claim 34, wherein thecompound is selected from the group consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. (1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; g.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; h.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;i.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;j.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;k.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;l.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;m.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;n. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; o.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene; p.2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene; q.2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; r.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; s.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; u.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; v.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; x.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; y.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; z.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; aa.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; ab.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; ac.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ad.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;ae.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;af.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand ag. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.36. The method of claim 34, wherein the compound is selected from thegroup consisting of: a.(1R,1S)-2-carbomethoxy-3-{((trifluoromethyl)sulfonyl)oxy}-8-oxabicyclo(3.2.1)-2-octene;b. (1R,1S)-2-carbomethoxy-3-phenyl-8-oxabicyclo(3.2.1)-2-octene; c.(1R,1S)-2-carbomethoxy-3-(4-fluorophenyl)-8-oxabicyclo(3.2.1)-2-octene;d.(1R,1S)-2-carbomethoxy-3-(4-chlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;e.(1R,1S)-2-carbomethoxy-3-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)-2-octene;f. 2-carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo(3.2.1)-2-octene; g.2-carbomethoxy-3-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)-2-octene andh. 2-carbomethoxy-3-(4-iodophenyl)-8-oxabicyclo(3.2.1)-2-octene.
 37. Themethod of claim 34, wherein the compound is selected from the groupconsisting of: a.(1R,1S)-2β-carbomethoxy-3β-phenyl-8-oxabicyclo(3.2.1)octane; b.(1R,1S)-2β-carbomethoxy-3α-phenyl-8-oxabicyclo(3.2.1)octane; c.(1R,1S)-2β-carbomethoxy-3β-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;d.(1R,1S)-2β-carbomethoxy-3α-(4-fluorophenyl)-8-oxabicyclo(3.2.1)octane;e.(1R,1S)-2β-carbomethoxy-3β-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;f.(1R,1S)-2β-carbomethoxy-3α-(4-chlorophenyl)-8-oxabicyclo(3.2.1)octane;g.(1R,1S)-2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;h.(1R,1S)-2β-carbomethoxy-3α-(3,4-dichlorophenyl)-8-oxabicyclo(3.2.1)octane;i. 2β-carbomethoxy-3α-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; j.2β-carbomethoxy-3β-(4-bromophenyl)-8-oxabicyclo(3.2.1)octane; k.2β-carbomethoxy-3α-(4-tributyltinphenyl)-8-oxabicyclo(3.2.1)octane; l.2β-carbomethoxy-3α-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; m.2β-carbomethoxy-3β-(4-nitrophenyl)-8-oxabicyclo(3.2.1)octane; n.2β-carbomethoxy-3β-(4-aminophenyl)-8-oxabicyclo(3.2.1)octane; o.2β-carbomethoxy-3β-(4-iodophenyl)-8-oxabicyclo(3.2.1)octane; p.2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; q.2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; r.2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane; s.2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane; t.2β-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;u.2β-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;v.2α-carbomethoxy-3α-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octane;w.2α-carbomethoxy-3β-{bis(4-fluorophenyl)methoxy}-8-oxabicyclo(3.2.1)octaneand x. 2-Carbomethoxy-3-(3,4-dichlorphenyl)-8-oxabicylo(3.2.1)octane.